Neuroendocrinology

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. 50.1 . Although numerous neurotransmitters and peptides can alter body temperature, their physiological roles remain unclear.

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 the 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 mediated by prostaglandin. Hypothermia, both acute and chronic, 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 α ₂ -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 causing 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. 50.2 . 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 ( ).

In response to a meal or to starving, hormonal and neural signals are generated in the periphery. Some are of short duration and others of long duration. Some relate to satiety, others relate to feeding behavior, and still others relate to “thinness and fatness.” Leptin is secreted by fat cells in the periphery and is sensed in the brain. Leptin seems to be most important if the levels fall below normal. In that circumstance it stimulates hunger. High levels of leptin tend not to suppress hunger. Neurons in the hypothalamus release the pro-opiomelanocortin (POMC) segment alpha-melanocyte–stimulating hormone (α-MSH), which suppresses appetite. Neurons that release agouti-related peptide (AgRP) also corelease neuropeptide Y (NPY) and γ-aminobutyric acid (GABA), both of which stimulate appetite ( ). Ghrelin, a stimulator of growth hormone (GH) release, is released from the stomach in the fasting state. Ghrelin activates NPY and agouti-related protein in the hypothalamus, leading to increased feeding and the deposition of energy into body fat. Peripheral insulin seems to mediate a satiety signal in the ventromedial hypothalamus. Destruction of the ventromedial hypothalamus, in both animals and humans, leads to obesity. Lesions in the paraventricular nucleus have a similar effect ( ). Overeating (hyperphagia) is only one of the mechanisms that produce hypothalamic obesity; more efficient handling of calories by the eater is probably another important factor. Hypothalamic lesions can also 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. Oral motor and meal-size responses may be dependent on centers in the caudal brainstem modulated by the hypothalamus.

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 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. GI peptides—such as cholecystokinin (CCK), 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. NPY 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 is probably not related to central changes in NPY.

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 the effects of endogenously secreted leptin.

When 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 MC ₄ R as a cause of their obesity ( ).

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

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, NPY, vasopressin, oxytocin, CCK, ghrelin, and leptin as well as the monoamines—serotonin, dopamine, and norepinephrine—have been found in patients with eating disorders ( ). These neurotransmitters play a role not only in appetite but also in mood and impulse control. The abnormalities have been found to persist, in some instances, long after recovery. Autoantibodies have been implicated in the eating abnormalities seen in this condition ( ). 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 of these syndromes.

Emotion, Libido, and Sexual Differentiation

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 HPA 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 HPA 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 the 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. Melanocortinergic agents may be useful in the treatment of sexual dysfunction in both males and females ( ).

Current understanding of the human hypothalamus in relation to normal development, sexual differentiation, and behavior is expanding gradually. Sexual differentiation of the genitals occurs during the first 2 months of pregnancy, whereas sexual differentiation of the brain does not occur until the second half of pregnancy. Gender identity appears to result from the developing brain being exposed to testosterone, resulting in a male direction if exposed or a female direction if not. In addition to brain differences related to gender, there are brain differences related to sexual orientation ( )

It has been known for some time that oxytocin, the classical posterior pituitary hormone that has effects on uterine contraction and milk letdown, works in the brain to promote social affiliation in humans. This brain effect is important for parent-infant bonding and romantic attachments (Feldman, 2012). It also offers hope for the treatment of some of the behavioral aspects of frontotemporal dementia ( ).

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 are usually 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 50.3 ), other peptides with putative regulatory functions are found in high concentration in the hypothalamus: neurotensin, substance P, CCK, NPY, vasoactive intestinal polypeptide, and the opioid peptides. The hypothalamus also is rich in acetylcholine, norepinephrine, dopamine, serotonin, histamine, and GABA. In many neurons, these neurotransmitters colocalize with peptides, although this colocalization 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. 50.3 ).

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 palsies of the third, fourth, fifth, and sixth cranial nerves. 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. Appropriate evaluation with computed tomography (CT) or magnetic resonance imaging (MRI) can identify these conditions.

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-orbital area. 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 normal-sized or expanded sella, and the sella contains mostly CSF. Only rarely can evidence of impairment of pituitary function be found in such patients. In cases of marked hydrocephalus, accompanying pituitary-hypothalamic dysfunction can be seen, presenting most commonly in females as amenorrhea.

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 Chapter 16, Chapters 45 ). 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. Because pressure on the optic chiasm preferentially affects the fibers subserving color vision, these visual field defects may be missed on bedside confrontation testing with the fingers. A better bedside test is to look for subtle color desaturation in the affected visual field.

Blood Supply

The superior and inferior hypophysial arteries are the pituitary’s major source of blood ( Fig. 50.4 ). The posterior pituitary gland is supplied principally by the inferior hypophysial arteries and 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 the regulation of hypothalamic-pituitary function.

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 50.3 ). 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 to participate in the coordination of anterior pituitary function with sleep, arousal, and general metabolism. This is well reviewed in an article by .

Abnormalities of Anterior Pituitary Function