Temperature Regulation

The hypothalamus plays a key role in ensuring that body temperature is maintained within narrow limits by balancing the heat gained from metabolic activity and the environment with the heat lost to the environment. A theoretical schema of the mechanisms of hypothalamic temperature regulation is depicted in Fig. 42.1. Although numerous neurotransmitters and peptides alter body temperature, their physiological roles remain unclear.

Fig. 42.1 Schematic representation of hypothalamic temperature regulation mechanisms. Preoptic anterior hypothalamus functions as a thermostat and contains mechanisms for regulation of heat loss. Posterior hypothalamus integrates heat production mechanisms. Lesions of the preoptic anterior hypothalamus result in hyperthermia; lesions of the posterior hypothalamus cause hypothermia or poikilothermia.

(Reprinted with permission from Cooper, P.E., Martin, J.B., 1983. Neuroendocrine disease, in: Rosenberg, R.N. (Ed.), The Clinical Neurosciences. Churchill Livingstone, New York.)

Hypothalamic injury can cause disordered temperature regulation. One potentially serious consequence is the hyperthermia that may occur when the preoptic anterior hypothalamic area is damaged or irritated by ischemia, subarachnoid hemorrhage, trauma, or surgery. In some patients, the marked impairment of heat-loss mechanisms and the resulting hyperthermia may be fatal. In those individuals who survive, temperature control usually returns to normal over a period of days to weeks. Chronic hyperthermia of hypothalamic origin is extremely uncommon; it may occur with continued impairment of ability to dissipate heat adequately or with difficulty sensing temperature elevations. Chronic hypothalamic hyperthermia does not respond to salicylates and other antipyretics because it is not prostaglandin mediated. Both acute and chronic hypothermia can be due to hypothalamic injury, the most common causes being head trauma, infarction, and demyelination. Other entities to be considered in the differential diagnosis are severe hypothyroidism, Wernicke disease, and drug effect. Some patients with no apparent hypothalamic structural abnormalities may have episodes of recurrent hypothermia. The cause of this syndrome is unclear, although the response of some patients to anticonvulsant agents and of others to clonidine or cyproheptadine suggests a possible neurotransmitter abnormality. Agenesis of the corpus callosum in association with episodic hyperhidrosis and hypothermia (Shapiro syndrome) is caused in some individuals by an abnormally low hypothalamic set point. These symptoms may respond to clonidine (a centrally acting α₂-adrenergic agonist). A similar condition associated with hyperthermia (so-called reverse Shapiro syndrome) has been found to respond with normalization of temperature to low-dose l-dopa; higher doses cause hypothermia. Large lesions in the posterior hypothalamus may impair both heat production (by altering the set point) and heat loss (by damaging the outflow from the preoptic anterior hypothalamic area). This results in poikilothermia, a condition in which body temperature varies with the environmental temperature.

Appetite

Given free access to food and water, most animals maintain their body weight within narrow limits. With a change in energy intake/expenditure (a change in the size or number of individual meals that is not balanced by an equal and opposite change in energy use), the animal experiences a change in weight. One possible model of nutrient balance is depicted in Fig. 42.2. The four components of energy balance are (1) the afferent system, (2) the CNS processing unit, (3) the efferent system, and (4) the absorption of food from the gut and its metabolism in the liver. Defects at any point in these systems may lead to weight loss or weight gain (Wynne et al., 2005).

Fig. 42.2 Sympathetic nervous system. In the regulation of energy balance, the brain is the central processing unit. It receives afferent neuronal signals from the vagus nerve, via the brainstem and hormonal signals—ghrelin (from the stomach), insulin (from the pancreas), and leptin (from adipocytes). The brainstem also has input to the hypothalamus via norepinephrine (NE) (from the locus ceruleus) and serotonin, or 5-hydroxytryptamine (5-HT) (from the raphe nuclei). These afferent signals are interpreted both in the brainstem (in the nucleus of the tractus solitarius) and in the hypothalamus (in the ventromedial nucleus). The ventromedial nucleus of the hypothalamus communicates with the lateral hypothalamic area (LHA) and the paraventricular nucleus (PVN) by means of pro-opiomelanocortin-cocaine/amphetamine-regulated transcript (POMC-CART), an anorexigenic peptide (the release of which is stimulated by insulin and leptin), and by neuropeptide Y/agouti-related protein (NPY/AGRP), an orexigenic peptide (the release of which is stimulated by ghrelin and inhibited by leptin and insulin)—or through the parasympathetic nervous system. Output from the LHA and PVN is either via the sympathetic nervous system, which leads to energy expenditure through physical activity, activation of β₂-adrenergic receptors, and uncoupling proteins in the adipocyte to cause energy release through lipolysis, or through the parasympathetic nervous system. Output via the vagus nerve leads to increased insulin secretion, which causes adipogenesis and energy storage. For a more complete explanation of this control of energy balance, the interested reader is directed to the article by Lustig (2001). DMV, Dorsal motor nucleus of the vagus; GI, gastrointestinal; NTS, nuclear tractus solitarius.

In response to a meal or to starving, hormonal and neural signals are generated in the periphery. Some are of short duration, and others are of long duration. Some relate to satiety, others relate to feeding behavior, and still others relate to “thinness and fatness.” Ghrelin, a stimulator of growth hormone (GH) release, is released from the stomach in the fasting state. Ghrelin activates neuropeptide Y and agouti-related protein in the hypothalamus, leading to increased feeding and deposition of energy into body fat. Peripheral insulin seems to mediate a satiety signal in the ventromedial hypothalamus. Leptin is the other component of the afferent system.

Destruction of the ventromedial hypothalamus, both in animals and in humans, leads to obesity. Lesions in the paraventricular nucleus have a similar effect. Overeating (hyperphagia) is only one of the mechanisms that produces hypothalamic obesity; more efficient handling of calories by the eater is probably another important factor. Hypothalamic lesions also can cause weight loss. Lesions in the dorsomedial nucleus lead to a reduction in body weight and fat stores, as do lesions in the lateral hypothalamus. Studies in the decerebrate rat suggest that oral motor and meal-size responses are dependent on centers in the caudal brainstem, on which the hypothalamus has only a modulatory effect (Grill and Kaplan, 2002).

Meal size and food intake are influenced by many different stimuli. Sensory cues such as the sight, aroma, and taste of food are major factors in dietary obesity. A decrease in blood glucose or a decrease in the oxidation of fatty acids in the liver stimulates the act of eating. Stomach distention gives rise to neural and hormonal signals that reduce food intake. Gastrointestinal peptides such as cholecystokinin, bombesin, and glucagon inhibit feeding by their actions on the autonomic nervous system, particularly the vagal nucleus. Increased fatty acid oxidation leads to higher levels of 3-hydroxybutyrate, which then acts on the hypothalamus to reduce food intake. Interference with any of these sensing systems in the CNS can lead to obesity. Neuropeptide Y infused into the ventromedial nucleus of the hypothalamus induces obesity, perhaps by inhibiting sympathetic drive and stimulating insulin release. Although this may explain obesity with hypothalamic lesions, obesity related to eating highly palatable food probably is not related to central changes in neuropeptide Y.

In animals, the ob, db, and fa genes play a role in the ability of adipose tissue to regulate feeding through a circulating factor. When the product of the ob gene, leptin, is administered peripherally to a genetically obese (ob/ob) mouse deficient in leptin, the animal reduces its intake of food, with a resulting decrease in body weight. The role of leptin in appetite regulation is complex. Leptin does not reverse the obesity seen in db/db mice and in obese humans. In these groups, serum leptin concentrations are higher than in subjects of normal weight, suggesting an insensitivity to endogenous leptin production.

When α-melanocyte-stimulating hormone (α-MSH) binds to its receptor in the hypothalamus, it causes satiety. Up to 5% of obese children have been found to have an abnormality of the α-MSH receptor, MC₄R, as a cause of their obesity (Lustig, 2001).

The orexins (hypocretins) are neuropeptides that play a role in energy balance and arousal (Ferguson and Samson, 2003). Narcolepsy is caused by failure of orexin-mediated signaling. Orexins are found in the hypothalamus, where they regulate sleep/wake cycles (Baumann and Bassetti, 2005), and in the GI tract, where they excite secretomotor neurons and modulate gastric and intestinal motility and secretion (Kirchgessner, 2002).

Anorexia nervosa and bulimia nervosa are clinical eating disorders of unknown etiology seen primarily in young women and girls. Anorexia nervosa is characterized by reduced caloric intake and increased physical activity associated with weight loss, a distorted body image, and a fear of gaining weight. Bulimia nervosa is characterized by episodic gorging followed by self-induced vomiting or laxative and diuretic abuse or dieting and exercise to reduce weight. Initially these syndromes were considered to be neuroendocrine in origin, then for many years, they were assumed to be purely psychiatric. Although malnutrition produces changes in neuroendocrine function, disturbances in corticotropin-releasing hormone (CRH), opioids, neuropeptide Y, vasopressin, oxytocin, cholecystokinin (CCK), and leptin as well as the monoamines—serotonin, dopamine, and norepinephrine—have been found in patients with eating disorders (Barbarich et al., 2003). These neurotransmitters play a role not only in appetite but in mood and impulse control. The abnormalities have been found to persist, in some instances, long after recovery. Furthermore, patients with anorexia nervosa seem to have an increased total daily energy expenditure because of their increased physical activity. All of this suggests a complex interaction between the psyche and the endocrine system as a cause for these syndromes.

Emotion and Libido

Experimental and clinical data support the hypothesis that interaction of the frontal and temporal lobes and the limbic system is necessary for normal emotional function. Lesion and stimulation experiments in cats have shown that rage reactions can be provoked from the hypothalamus. In humans, electrical stimulation of the septal region produces feelings of pleasure or sexual gratification, whereas lesions of the caudal hypothalamus or manipulation of this area during surgery may cause attacks of rage. The amygdala (with its rich input from polysensory areas and limbic-associated areas and its output to the hypothalamus) and other subcortical areas are important structures through which the external environment can influence and cause emotional responses. In depression, activation of the hypothalamic-pituitary-adrenal axis has been recognized, but the story is more complex than this simple observation. Data have shown that depressed patients with suicidal ideation have less activation of the hypothalamic-pituitary-adrenal axis, whereas those who commit suicide have a more active axis. Unfortunately, many of these data are derived from peripheral tests that primarily examine pituitary function rather than assessing true hypothalamic function.

Libido, like other feelings, requires the participation of both hypothalamic and extrahypothalamic sites. In most instances of hypothalamic disease, loss of libido is caused by impaired release of gonadotropin-releasing hormone (GnRH) and a subsequent decrease in testicular testosterone in men. In women, libido is related more to adrenal androgens, and in menstruating women to ovarian androgens. Adrenal androgen levels may be low in women with corticotropin (i.e., adrenocorticotropic hormone [ACTH]) deficiency and secondary adrenal insufficiency. Hypersexuality associated with hypothalamic disease is rare and may occur with or without a subjective increase in libido. The melanocortins (ACTH and α-, β-, and γ-MSH) may play a role in the motivational aspects of sexual behavior, as well as having a sildenafil-like effect on penile and vaginal blood flow, albeit through a central rather than a peripheral mechanism (Raffin-Sanson et al., 2003).

Current understanding of the human hypothalamus in relation to normal development, sexual differentiation, aging, and some degenerative neurological disorders is gradually expanding. The sexually dimorphic nucleus, or intermediate nucleus, of the preoptic area is twice the volume in male subjects compared to that in female subjects—although this finding is disputed by some investigators. Two other cell groups in the preoptic anterior hypothalamus are larger in males than in females. The size does not differ between homosexual and heterosexual men. Although the shape of the suprachiasmatic nucleus differs in male and female subjects, the vasopressin cell number and volume are similar in men and women. Homosexual men seem to have a larger suprachiasmatic nucleus containing twice as many cells as in heterosexual men (Swaab et al., 2001). The site of the central nucleus of the bed nucleus of the stria terminalis is perhaps involved in gender identity in transsexuals. At present, the significance of these observations is uncertain.

It has been known for some time that oxytocin, the classical posterior pituitary hormone, works in the brain to promote mother-infant bonding. Now, it has been shown that it can promote more appropriate social behavior and affect in patients with high-functioning autism or with Asperger syndrome (Andari et al., 2010).

Biological Rhythms

Most endocrine rhythms are circadian—that is, a complete cycle takes approximately 24 hours. Although longer and shorter cycles do occur, the circadian rhythms have been studied most extensively. In many animals, light plays an important role in regulating circadian rhythms. Nerve fibers project from the optic chiasm to the suprachiasmatic and arcuate nuclei of the hypothalamus. The hypothalamus is responsible for the hormonal rhythms, such as cortisol and GH secretion, and for the behavioral rhythms, such as sleep/wake cycles and estrous activity. Although patients with hypothalamic disease often have disturbances in their biological rhythms, these usually are of less clinical importance than other problems caused by such lesions, and this is seldom if ever a presenting complaint.

Functional Anatomy

In humans, discernible hypothalamic-pituitary tissue begins to develop during week 5 of embryonic life. The Rathke pouch, a diverticulum of the buccal cavity, forms and expands dorsally to contact and invest the diverticulum that develops from the floor of the third ventricle. By week 11, the buccal tissue has lost its connection with the foregut and has flattened to form the primitive anterior pituitary, whereas the neural tissue from the floor of the third ventricle is forming the posterior pituitary. Residual Rathke pouch tissue is postulated to give rise to the craniopharyngiomas that can occur in this region. Rarely, ectopic functional pituitary tissue in the oropharynx can cause signs and symptoms of hyperpituitarism.

The hypothalamus, despite its small size, is the region of brain with the highest concentrations of neurotransmitters and neuropeptides. Beginning with the pioneering work of Ernst and Berta Scharrer and Geoffrey Harris in the 1940s, the hypothalamus has been assigned a central role in regulating anterior pituitary function. In addition to the identified hypophysiotropic hormones (Table 42.3), other peptides with putative regulatory functions are found in high concentration in the hypothalamus: neurotensin, substance P, cholecystokinin, neuropeptide Y, vasoactive intestinal polypeptide, and the opioid peptides. The hypothalamus also is rich in acetylcholine, norepinephrine, dopamine, serotonin, histamine, and γ-aminobutyric acid (GABA). In many neurons, these neurotransmitters co-localize with peptides, although this co-localization and presumptive co-release have uncertain physiological significance. In patients with nonfunctioning pituitary or parapituitary tumors, symptoms produced by compression of neural structures adjacent to the pituitary gland are a common presentation. Understanding these symptoms requires knowledge of the anatomy of the region (Fig. 42.3).

Table 42.3 Hypothalamic Peptides Controlling Anterior Pituitary Hormone Release

Fig. 42.3 Diagrammatic representation of the anatomical relations 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 (the ophthalmic and maxillary nerves), third nerve (oculomotor), fourth nerve (trochlear), and sixth nerve (abducens). The optic chiasm and optic tract are located superior and lateral, respectively, to the pituitary.

(Drawing by B. Newberg. Modified from Makwell, A.K., 1973. Gray’s Anatomy, thirty-fifth ed. Saunders, Philadelphia.)

Tumor erosion of the floor of the sella turcica may lead to cerebrospinal fluid (CSF) rhinorrhea. Conversely, sinusitis or sphenoid sinus mucocele can invade the sella, resulting in anterior pituitary dysfunction. Expansion of pituitary tumors into the cavernous sinus can produce a variety of upper cranial nerve palsies. The development of such deficits is especially common with the sudden expansion of pituitary tumors that occurs in pituitary apoplexy. Carotid aneurysms or ectatic carotid arteries in the cavernous sinus may expand medially and mimic pituitary adenomas by enlarging the sella and causing anterior pituitary hypofunction.

The dura overlying the sella is sensitive to pain, and stretching of this structure by expanding pituitary tumors gives rise to headache referred to the vertex and retro-orbitally. In some cases, especially if intracranial pressure is elevated, the dura may herniate into the sella, where continued pulsation of the CSF over time leads to remodeling and expansion of the sella. This produces the radiological finding of the empty sella syndrome, another cause of which is lymphocytic hypophysitis. The pituitary gland becomes a thin ribbon of tissue along the walls of the expanded sella, and the sella contains mostly CSF. Only rarely can evidence of impairment of pituitary function be found in such patients.

Expansion of pituitary tumors out of the sella tends to lead to compression of the anterior and inferior crossing fibers of the optic chiasm (see Chapters 14 and 36). These fibers subserve vision in the superior temporal quadrants. Therefore, pituitary adenomas typically cause bitemporal superior quadrantanopias. Lesions such as craniopharyngiomas that impinge on the posterior and superior fibers of the optic chiasm tend to manifest with bitemporal inferior quadrantanopias. Nevertheless, owing to the variability of the positioning of the optic chiasm and the tendency for tumors to be asymmetrical in their growth, parasellar lesions result in a wide variety of field defects.

Blood Supply

The superior and inferior hypophysial arteries are the pituitary’s major source of blood (Fig. 42.4). The posterior pituitary gland is supplied principally by the inferior hypophysial arteries and is drained by the inferior hypophysial veins. The superior hypophysial artery forms a primary capillary plexus in the median eminence of the hypothalamus. From here, blood flows into the long hypophysial portal veins, which carry it to the anterior pituitary. Although some blood from the anterior pituitary drains into the cavernous sinus, some drains into the posterior pituitary, and some returns to the median eminence by way of the long portal veins, which are capable of bidirectional blood flow. This vascular anatomy provides a potential mechanism for the important feedback loops necessary for regulation of hypothalamic-pituitary function.

Fig. 42.4 Blood supply of the median eminence and pituitary gland.

(Reprinted with permission from Cooper, P.E., Martin, J.B., 1983. Neuroendocrine disease, in: Rosenberg, R.N. (Ed.), The Clinical Neurosciences. Churchill Livingstone, New York.)

Hypothalamic Control of Anterior Pituitary Secretion

The hypothalamus produces hypophysiotropic substances that control the secretion of anterior pituitary hormones. Five neuropeptides and one neurotransmitter (dopamine) are known to be important physiological regulators of pituitary function (see Table 42.3). In addition, several neurotransmitters affect pituitary hormone release, although their physiological role remains uncertain. Since their discovery in 1998, the orexins (hypocretins) have been found to regulate virtually all the hypothalamic-pituitary axes as well as participate in the coordination of anterior pituitary function with sleep, arousal, and general metabolism. This is well reviewed in a recent article by López, Tena-Sempere and Diéguez (2010).

Abnormalities of Anterior Pituitary Function

Pituitary Tumors and Pituitary Hyperplasia

Pituitary tumors account for approximately 15% of all intracranial tumors. Although most are benign, they can be locally invasive. Only rarely is true malignancy evidenced by metastases. The old classification of pituitary adenomas into chromophobe, acidophil, and basophil has been supplanted by a more functional classification based on findings of immunological and electron microscopic examinations (Table 42.5). Hyperplasia of various cellular elements of the pituitary is relatively rare and usually only seen in cases of ectopic hypothalamic-releasing hormone production (Ironside, 2003).

Table 42.5 Classification of Pituitary Adenomas

Modified with permission from Thapar, K., Kovacs, K., Muller, P.J., 1995. Clinical-pathological correlations of pituitary tumours. Clin Endocrinol Metab 9, 243-270.

Most pituitary tumors that have been removed surgically and examined have been found to be monoclonal in origin. This finding suggests that a majority of pituitary tumors arise from a single cell in which a mutation either activated a proto-oncogene or inactivated a tumor suppressor gene. Almost half of pituitary tumors show aneuploidy (usually more or [rarely] fewer than the normal number of chromosomes). The significance of this to tumor formation is uncertain. The cell cycle inhibitory proteins, p14ARF and p16^INK4a, are coded for by the CDKN2A (cyclin-dependent kinase inhibitor) gene. This gene has been found to have reduced expression in a majority of human pituitary tumors. PTTG (pituitary tumor–transforming gene) expression is increased in certain human pituitary tumors, but whether these changes in gene expression play a role in tumor induction or whether they are the result of tumor formation is unclear.

The G proteins are a family of proteins comprising α, β, and γ subunits that bind to guanine nucleotides. A variety of mutations involving single amino acid substitutions in the portion of the Gs gene that encodes the Gs α subunit have been identified in nearly 40% of GH-secreting tumors. These mutations inhibit the breakdown of the α subunit, thereby mimicking the effect of specific growth factors and leading to increased adenylate cyclase activity and elevated intracellular cyclic adenosine monophosphate levels. Nevertheless, no single mutation or alteration of function seems to explain tumor formation in more than the occasional case. Somatostatin inhibits both GH and cyclic adenosine monophosphate production, and this may be the mechanism by which it shrinks GH-secreting pituitary tumors.

Levy and Lightman (2003) suggest that although some pituitary tumors may be due to genetic abnormalities, it is possible that a majority of pituitary tumors are not “tumors” in the usual sense but rather represent an overresponse to normal trophic factors that has failed to normalize once the growth stimulus has returned to normal.

Other Tumors

Gliomas, meningiomas, chordomas, teratomas, and dermoid and epidermoid tumors all can occur in the region of the sella turcica, and local compressive effects may produce a clinical picture resembling that of primary pituitary tumors. The pituitary gland is the site of metastatic deposits in 4% of cancer patients. Usually these metastases are asymptomatic; when symptoms do occur, however, they most often are related to disturbance of posterior pituitary function.

Craniopharyngiomas are only one-third as common as pituitary tumors. They are thought to arise from residual rests of Rathke pouch tissue. Most commonly found in a suprasellar location, they also occur anywhere along the pituitary-hypothalamic axis, including within the sella. Craniopharyngiomas can appear at any age; however, approximately a third of cases arise before the age of 15 years. Because these tumors produce no hormones, patients usually present with signs of local compression, especially of the visual system, or with hypothalamic dysfunction such as growth failure or diabetes insipidus (DI). Almost half of affected children show evidence of growth failure. Three-fourths of patients, both adults and children, have visual symptoms.

Hypophysitis

Hypophysitis from infection or granulomatous disease such as sarcoidosis can result in hypopituitarism. Lymphocytic hypophysitis, a sterile inflammation of the pituitary of probable autoimmune origin, is seen almost exclusively in women, particularly during pregnancy. Usually it causes hypopituitarism, although it can cause hyperprolactinemia and may be a cause of the empty sella syndrome.

Physiology

Diabetes Insipidus

Diabetes insipidus (DI) is a clinical syndrome characterized by severe thirst, polydipsia, and polyuria. Central DI must be distinguished from nephrogenic DI (an inability of the kidney to respond to ADH) and from compulsive water drinking (Baylis, 1995). Distinguishing among these entities normally is done using a water deprivation test. A urine osmolality of greater than 750 mmol/L after water deprivation excludes the diagnosis of DI. Central DI is characterized by an increase in osmolality to greater than 750 mmol/L after administration of desamino-d-arginine-vasopressin (DDAVP). In nephrogenic DI, little change in osmolality occurs after DDAVP administration. The polyuria induced by chronic compulsive water drinking may produce a renal tubular concentrating defect because of medullary washout—that is, the loss of sodium and other solutes from around the loops of Henle. This can make it difficult to differentiate partial DI of central or renal cause from polydipsia. Treatment by gradual fluid restriction, with or without DDAVP, can be used to reverse the medullary washout, thereby increasing the sensitivity of the test.

The water deprivation test must be strictly supervised by a physician familiar with the technique. Severe and potentially fatal dehydration can occur rapidly in patients with complete DI, especially children. Similarly, patients with compulsive water drinking given DDAVP and allowed access to water can drink themselves into hyponatremic coma.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

Cerebral Salt Wasting

Some patients with hyponatremia do not have SIADH secretion with resultant retention of renal free water. Instead, they have an inappropriate natriuresis. Hyponatremia, accompanied by renal sodium loss and volume depletion, occurs in patients with primary cerebral tumors, carcinomatous meningitis, subarachnoid hemorrhage, head trauma, and after intracranial surgery and pituitary surgery. Unlike patients with SIADH, these patients respond to vigorous sodium and water replacement, and their condition actually is worsened by fluid restriction. This inappropriate natriuresis that accompanies intracranial disease (so-called cerebral salt wasting) may be caused either by a natriuretic hormone such as atrial natriuretic peptide or by an alteration of the neural input to the kidney.

It is critical to distinguish between these patients and those with SIADH, because the treatment for SIADH worsens the hyponatremia of cerebral salt wasting. Differentiation is best done by a careful assessment of volume status using clinical and laboratory examinations to detect signs of volume depletion. If the diagnosis is uncertain, fluid restriction should be instituted. Then, if the natriuresis persists in the face of volume restriction, the syndrome of cerebral salt wasting should be suspected and appropriate therapy initiated. Because either syndrome can develop in patients undergoing pituitary surgery, it is very helpful to know the patient’s presurgical weight. This makes it much easier to determine their postsurgical volume status.

History and Physical Examination

Patients with suspected hypothalamic or pituitary disorders should be questioned specifically about dysfunction of the nonendocrine aspects of the hypothalamus: appetite, body temperature, sleep/wake cycles, emotion, libido, and autonomic nervous system function. Such symptoms may point to a hypothalamic rather than a pituitary location. A careful functional inquiry also should cover clinical aspects of the hyperfunction and hypofunction of each of the anterior and posterior pituitary hormones.

Because of the proximity of the optic nerves to the hypothalamic-pituitary unit, a careful examination of the visual fields is essential (see Chapters 14 and 36).

Assessment by Imaging Studies

Magnetic resonance imaging has generally replaced CT scanning as the investigation of choice in the diagnosis of pituitary and parapituitary lesions. The use of MRI with gadolinium contrast is associated with a detection rate for pituitary tumor of 82% to 94%. With use of two-dimensional techniques, it is important to obtain thin (1- to 2-mm) coronal slices of the sella to achieve the best results. Cerebral angiography is rarely required, because large cerebral aneurysms mimicking pituitary adenomas are readily picked up by MRI. Angiography is reserved primarily to demonstrate the blood supply of suspected meningiomas, and very often this information can be gathered from CT angiography.

Endocrinological Investigation

Not every patient with hypothalamic-pituitary disease requires a full battery of pituitary tests. In general, the endocrinological investigation is aimed at determining the extent of pituitary functional damage if any and—in patients whose blood levels of hormones are elevated or in whom excessive hormonal secretion is suspected on the basis of clinical features—determining whether the hormones in question respond normally to physiological suppressors and stimulators.

No single endocrine test can provide all the answers about pituitary function. Conclusions are based on a synthesis of evidence gained from clinical examination, endocrine tests, and MRI. Endocrine testing is used to determine residual pituitary function after surgery or radiotherapy. The return of biochemical markers of abnormal pituitary secretion or their failure to resolve can be used to gauge the success of surgery and aid in differentiating scar tissue from tumor recurrence on postoperative MRI scans. Table 42.6 summarizes some of the more common pituitary tests and their use.

Table 42.6 Common Tests of Pituitary Function

ACTH, Adrenocorticotropic hormone (corticotropin); FSH, follicle-stimulating hormone; IV, intravenously; LH, luteinizing hormone; PO, orally.

Treatment of Pituitary Tumors

Treatment of Hypopituitarism

Vasopressin, ACTH, and TSH are the pituitary hormones critical to health and well-being. The management of vasopressin deficiency has been discussed already. ACTH deficiency is managed by glucocorticoid replacement; mineralocorticoid supplementation is seldom necessary in patients with ACTH deficiency. Most patients require 5 mg of prednisone (or 20 mg of hydrocortisone) each morning, and some require an additional 2.5 mg of prednisone (or 10 mg of hydrocortisone) in the evening. With the development of mild intercurrent illness, the dose of steroid should be doubled. Corticosteroid replacement in the glucocorticoid-deficient patient with serious illness or undergoing surgery consists of hydrocortisone sodium succinate, 10 mg/h IV around the clock. As the patient recovers, the dose is slowly tapered to maintenance levels.

Thyroid-stimulating hormone deficiency is managed by levothyroxine (l-thyroxine) replacement. Suppression of elevated TSH cannot be relied on to determine the adequacy of replacement in patients with pituitary-hypothalamic disease. Resolution of the clinical signs and symptoms of hypothyroidism is the important goal. In patients who receive adequate replacement, so that triiodothyronine (T₃) levels in the upper half of the therapeutic range are achieved, thyroxine (T₄) levels often are at or above the upper limit of normal.

Gonadotropin deficiency usually is managed by administration of testosterone or estrogen. This therapy, however, does not restore fertility. In patients for whom fertility is sought, a consultation with a reproductive endocrinologist and administration of various substitution therapies for LH and FSH may allow induction of fertility.

Growth hormone deficiency in children is treated by the administration of synthetic GH. GH-deficient adults currently do not routinely receive GH replacement. The evidence suggests that muscle strength, wound healing, and lean body mass all are improved by treatment with synthetic GH. Unfortunately, these studies have been short term, and the dose of GH required for long-term replacement is unknown. Because of the potentially deleterious effects of excessive levels of GH, studies are underway to determine appropriate replacement doses. No therapy is available for prolactin deficiency.

Pheochromocytomas

Pheochromocytomas are rare tumors that arise most commonly (85% to 90% of the time) from the catecholamine-producing cells of the adrenal medulla; they also can arise from extraadrenal chromaffin tissue in the cervical and thoracic regions and in the abdomen. A majority of these tumors develop spontaneously; however, they can be part of other syndromes such as multiple endocrine neoplasia types II and IIb, von Hippel-Lindau disease, neurofibromatosis, ataxia-telangiectasia, tuberous sclerosis, and Sturge-Weber syndrome.

Pheochromocytomas secrete predominantly norepinephrine, epinephrine, and some dopamine. These compounds are responsible for the most common signs and symptoms of pheochromocytoma: throbbing headache, sweating, palpitations, pallor, nausea, vomiting, and tremor. Pheochromocytomas also are capable of secreting other neuropeptides that can be responsible for different clinical symptoms. Pheochromocytoma should be suspected in patients with progressive or malignant hypertension, hypertension of early onset without family history, hypertension resistant to conventional therapy, paradoxical worsening of hypertension in response to treatment with beta-blockers, and a history of pressor response provoked by anesthesia, labor or delivery, or angiography. We screen for pheochromocytoma by collecting two consecutive 24-hour urine specimens and having them analyzed for vanillylmandelic acid, norepinephrine, epinephrine, metanephrine, normetanephrine, and dopamine. Ideally, these collections should be done around the time when the patient is symptomatic, because periodic hormone secretion does occur, and levels may at times be normal. The completeness of the 24-hour collection should be confirmed by an analysis of urinary creatinine. Sensitivity and specificity of testing can be enhanced by adding an assay of plasma catecholamines.

Tumor localization usually can be achieved by CT scanning of the adrenals. If a wider search is necessary, MRI may be more helpful. Radiolabeled metaiodobenzyl guanidine (¹²³I-MIBG), an iodinated guanethidine derivative, is taken up by chromaffin tissue, and its use with single-photon emission computed tomography (SPECT) can be helpful in localizing nonadrenal tumors and metastases. Some centers have been using indium 111–labeled pentetreotide, an analog of somatostatin, to localize somatostatin receptors on these tumors; 6-¹⁸F-fluorodopamine and [¹¹C]hydroxyephedrine PET scanning also are complementary techniques for tumor localization (Eriksson et al., 2005).

Patients with pheochromocytoma should be managed in centers with previous experience in treating this type of tumor. Suitable preoperative preparation is necessary to prevent hypertensive or hypotensive crisis during surgery. For benign tumors, complete surgical removal is the treatment of choice. For malignant tumors, palliative management is indicated using a variety of treatments.

Carcinoid Tumors

Carcinoid tumors arise from enterochromaffin cells in the GI tract, pancreas, or lungs and only rarely from the thymus or gonads. When carcinoid tumors release biogenic amines directly into the systemic circulation, bypassing the liver, the carcinoid syndrome results. This syndrome is characterized by episodes of flushing, often with accompanying diarrhea or asthma. Later in the syndrome, fibrosis of the endomyocardium develops. Carcinoid tumors may be a source of ectopic ACTH, CRH, or GHRH secretion.

The diagnosis is made by finding elevated urinary 5-hydroxyindoleacetic acid levels. As in pheochromocytoma, carcinoids also secrete peptides (e.g., kallikrein, substance P, neurotensin) and other amines (e.g., histamine, dopamine), and some of these substances may be responsible for the flushing that occurs in the syndrome. To localize these tumors, [¹¹C]5-hydroxytryptophan and [¹¹C]l-dihydroxyphenylalanine can be useful in PET scans.

Surgery is the treatment of choice, but by the time the tumors become symptomatic, they often are incurable, because liver metastases are required for the appearance of symptoms. Serotonin antagonists may be used to relieve some of the symptoms, and octreotide may successfully manage carcinoid crisis. Radiolabeled octreotide is being used in some centers for palliative management of these tumors.