What gland stores but does not produce hormones?

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Figure 2.1
Circuitry of the Hypothalamic-neurohypophyseal tract.

The Neuroendocrine System represents the second, and last, major efferent system of the hypothalamus that we will consider in detail in this section. The third efferent system, the limbic system, will be covered in a later chapter. The information transfer in the hypothalamic-neuroendocrine pathways are unique in that they are largely blood borne as opposed to neurally mediated. Traditionally, the neuroendocrine system has been considered in two parts, that part dealing with the posterior pituitary, or neurohypophysis; and that part dealing with the anterior pituitary, or adenohypophysis. However, it is increasingly clear that the immune system also has such an important effect on neuroendocrine regulation that it must now also be considered as a special “diffuse” neuroendocrine component.

The posterior pituitary is often termed the neurohypophysis because the hormones of this part of the pituitary are released directly from the axonal endings of their source neurons into the circulation (Figure 2.1). The hypothalamic nuclei in which the cell bodies of these neurons reside are the supraoptic and the paraventricular nuclei. As we discussed in the previous chapter, both nuclei are composed of multiple cell types, but it is only the large magnocellular neurons that produce the hormones and that send axons into the neurohypophysis. The pathway from the hypothalamus to the posterior pituitary is called the hypothalamo-neurohypophyseal tract. It is along this tract that the hormones oxytocin and vasopressin (also called antidiuretic hormone or ADH) are cleaved from their prohormones and prepared for release in vesicles along with their co-peptides neurophysin I (oxytocin) and neurophysin II (vasopressin). Although the two amino acid peptides (nonapeptides) only differ by two amino acids, a given neuron produces only one or the other type of hormone at a time, but not both simultaneously. Release of hormones into the circulation of the posterior pituitary occurs following various neural stimuli and so the functions of this portion of the neuroendocrine system is characterized by reflexes with neural input and hormonal output.

Figure 2.2
Schematic of oxytocin roles in the milk let-down, parturition, and sperm transport reflexes.

Oxytocin. Oxytocin has no diurnal rhythm but is released in three reflexes following the influence of several different types of stimuli.

In the milk let-down reflex (Figure 2.2) the tactile stimuli applied to the breast by the suckling infant are transmitted to the hypothalamus by the spinohypothalamic tract directly to the preoptic and paraventricular nuclei to excite the magnocellular neurons and so provoke the release of hormone into the circulation. Oxytocin travels through the bloodstream acts on the mammary glands to cause milk release so that about 13 seconds later milk enters the ducts of the gland. Other non-tactile stimuli can also provoke this reflex including the sound of the baby crying, visual cues, anxiety, and other stimuli that increase hypothalamic sympathetic tone.
During parturition oxytocin induces powerful contractions of the uterine myometrium (Figure 2.2). Parturition itself is not induced by oxytocin, but the strength and frequency of the contractions of labor are enhanced by oxytocin. Pressure on the cervix or uterine wall are transmitted to the hypothalamus by the spinohypothalamic tract inducing hormone release as above which enters the blood acting to enhance contractions and so closing a positive feedback loop. Once the baby is born the cervical pressure is released and contractions cease. Synthetic oxytocin (Pitocin) is often given to increase uterine tone and control uterine bleeding following birth and after some gynecological procedures.
Oxytocin also produces contractions of the uterine myometrium and smooth muscles of the male and female reproductive tract that are important for sperm transport. The stimuli in this reflex are inputs from CNS sympathetic pathways activated with sexual activity.

Vasopressin. Vasopressin, also known as arginine vasopressin (AVP), acts on V2 receptors on the contraluminal surface of the distal tubular epithelium primarily in the collecting duct of the kidney to increase permeability and allow reabsorption of water and electrolytes into the circulation (Figure 2.3). Vasopressin has a diurnal peak late at night and early in the morning and a trough in the mid-afternoon. Sensors for plasma osmolality control the evoked secretion of vasopressin by magnocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus. The magnocellular neurons have intrinsic osmoreceptors in their plasma membrane and also receive afferent inputs from osmo-sensitive neurons in the organum vasculosum of the lamina terminalis. Sensors in the subfornical organ for angiotensin II also stimulate the release of vasopressin. Angiotensin II in the blood is elevated following the release of renin from the kidney in response to a decrease in blood pressure. Finally, the carotid and aortic arch bodies that signal the hypothalamus via the vagus and glossopharyngeal nerves via relay in the solitary nucleus also detect a decrease in blood oxygen or pressure and promote the release of vasopressin.

Figure 2.3
Schematic of vasopressin roles in plasma osmolality control reflexes

Oxytocin: No disorders have been acknowledged.
Diabetes Insipidus results due to insufficient vasopressin secretion in response to normal physiologic stimuli (central or neurogenic diabetes insipidus) or due to failure of the kidney to respond to vasopressin (nephrogenic diabetes insipidus). Neoplastic or infiltrative lesions, pituitary or hypothalamic surgery, severe head injuries, and idiopathic causes in that order most frequently cause central diabetes insipidus. The second two may remit spontaneously due to revascularization of the hypothalamo-pituitary stalk. The symptoms include large amounts of dilute urine, dehydration and thirst. Treatment is by hormone replacement.
Syndrome of Inappropriate AVP Secretion (SIADH) is associated with some central nervous system disorders including trauma, encephalitis, cerebrovascular accident and acute psychosis. Some drugs, including vincristine, some general anesthetics and antidepressants release or potentiate the effects of vasopressin. Elevated vasopressin also occurs in some tumors following ectopic synthesis and release. Clinical signs include hyponatremia, edema, hypovolemic features, hyperosmolality of the urine, and hyperlipidemia. Treatment requires fluid restriction and then identification and treatment of the underlying cause.

Figure 2.4
Schematic of the Tuberoinfundibular tract.

The Anterior Pituitary is an endocrine gland controlled by the hypothalamus in several fundamentally different fashions than is the posterior pituitary. None of the six major hormones released by the adenohypophysis are of hypothalamic origin, rather all are synthesized in cells embryonically derived from Rathke’s pouch in the anterior pituitary itself and released directly into the blood stream. Releasing- and release-inhibiting hormones that are synthesized in the arcuate, paraventricular, periventricular and supraoptic nuclei of the hypothalamus control anterior pituitary hormone secretion. Parvocellular neurons in these nuclei send their axons into the tuberoinfundibular tract and terminate on a capillary bed of the superior hypophyseal arteries located around the base of the median eminence. A given parvocellular neuron may release one or more releasing factor into these capillaries that coalesce into 6 to 10 small straight veins that form the hypophyseal-portal blood circulation which descends along the infundibular stalk and forms a second capillary plexus around the anterior pituitary. The releasing-hormones gain access to the five distinct types of target cells in the anterior pituitary from this plexus and stimulate anterior pituitary hormone release back into the capillary bed that then drains into the systemic circulation and transports the hormones to peripheral target tissues. The target tissues are stimulated to produce final mediator hormones that induce the physiological changes in peripheral tissues typical of each hormone.

Figure 2.5
Schematic of feedback control loops regulating the release of hypothalamic releasing factors and anterior pituitary hormones.

Control of secretion of the releasing factors, pituitary hormones and peripheral endocrine hormones is tightly inter-related in a set of feedback loops (Figure 2.5). The ultra-short feedback loop is mediated by the hypothalamic releasing factors limiting their own release by a type of autocrine effect on targets in the hypothalamus. Inhibition of releasing-factor secretion by pituitary hormones comprises short loop feedback. Finally, peripheral hormone inhibition of pituitary secretion comprises the direct long-loop feedback and inhibition on hypothalamic secretion of the releasing factors comprises the indirect long-loop feedback.

Figure 2.6
Detailed schematic of control loops in the
Growth Hormone pathway.

Growth hormone (GH) is secreted from somatotrophs, which comprise about half of the cells in the anterior pituitary (Figure 2.6). GH release is characteristically pulsatile being very low most of the day except following meals, exercise, during slow wave sleep, and at other individualized intervals. GH is necessary for normal linear growth and greatly influences intermediary metabolism by way of its induction of somatomedins (insulin-like growth factors, IGF) from target tissues most notably including the liver, chondrocytes, kidney, muscle, pituitary and the gastrointestinal tract. The hypothalamic regulation of GH secretion is illustrative of the mechanisms that govern all hormones of the anterior pituitary. Release is controlled by Growth hormone releasing hormone (GHRH) a 39 amino acid peptide that is primarily synthesized in the arcuate nucleus. GHRH release from the arcuate nucleus is stimulated by inputs from other brain regions using the neurotransmitters norepinephrine, dopamine, serotonin, acetylcholine and the enkephalins. Release of GHRH is inhibited by somatostatin and very importantly, by the actions of GH and IGF. The regulation of GHRH release by somatostatin is an example of ultra-short loop feedback, regulation of release by GH is an example of short-loop feedback, and regulation by IGF is an example of indirect long loop feedback.

Prolactin. Prolactin is necessary for lactation and is secreted by pituitary lactotrophs, which constitute 15 to 20 percent of the cells in the normal pituitary. Control of prolactin secretion by the hypothalamus is unique to that of the other anterior pituitary hormones in that under normal circumstances it is restrained and not elicited. Dopamine released from the arcuate and paraventricular nuclei acts on D2 receptors to increase adenyl cyclase in lactotrophs and inhibit prolactin release. Increases in plasma prolactin induces increased levels of dopamine in the arcuate and paraventricular nuclei and so establishes short-loop feedback.

Luteinizing hormone and follicle-stimulating hormone control the gonads in men and women. These hormones are secreted by the gonadotrophs, which comprise about 10 percent of the adenohypophysis. Luteinizing hormone-releasing hormone (LHRH) is the hypothalamic factor that controls release of the gonadotrophs and primarily is released itself from the arcuate nucleus. Feedback regulation of LHRH is provided by low levels of estrogen in females and by testosterone in males.

Thyroid-stimulating hormone (TSH) is secreted by about 5 percent of the cells in the pituitary called thyrotrophs and regulates thyroid function. Thyrotropin-releasing hormone (TRH) is found in the highest concentrations in the medial division of the paraventricular nucleus. The thyroid hormones thyroxine (T4) and triiodothyronine (T3) inhibit TSH production and release at the level of the pituitary (direct long loop) and inhibit the release of TRH at the level of the hypothalamus (indirect long loop).

Adrenocorticotropin (ACTH) controls glucocorticoid function of the adrenal cortex. ACTH is produced by the corticotrophs that comprise the remaining 15 percent of pituitary cells as part of the larger pro-opiomelanocortin gene product from which γ-melanocyte stimulating hormone and ß-endorphin are also derived. ACTH is released in pulses with an overall circadian rhythm peak at around 4 AM and a trough in the early evening. Corticotropin releasing-factor (CRH) is the primary but not the only hypothalamic factor that regulates ACTH release. CRH is primarily found in the paraventricular nucleus. The release of both ACTH and CRH are inhibited by the hormone cortisol secreted from the adrenal, and the release of both are strongly stimulated by stress.

Disorders of every hormone of the anterior pituitary have been identified and are characterized by either a hypo-secretion or over-secretion following various lesions, trauma, or tumors.

2.3 The Hypothalamic-Immune System-NeuroEndocrine Axis

Important bi-directional interactions between the immune system and the nervous and neuroendocrine systems have become defined over the past twenty years (Figure 2.8). These interactions account for modification of immune system function by nervous system activity and contrawise, modification of behavior, metabolism and neuroendocrine function by activity within the immune system compartment. The cascade of behavioral responses induced by activation of the immune system is termed the acute phase response, while the influence of brain activity on immunity has been termed psychoneuroimmunology.

Figure 2.8
Schematic of the Hypothalamic-Immune System-Neuroendocrine Axis.

Figure 2.9
Detailed schematic of IL-1 mediated components of the acute phase response.

The Acute Phase Response. The acute phase response is a constellation of behavioral and physiological changes that occur following invasion of the body by pathogens or tissue injury that we know as “feeling sick”, and thus also called sickness behavior. Fever is one component of the acute phase response (see previous chapter). Other components include an increase in slow wave sleep, anorexia, affective and cognitive impairment, decreased social and sexual behavior and lowered pain threshold. In addition, there are changes in blood chemistry including an increase in C-reactive protein, haptoglobin, serum amyloid A, a2-macroglobulin, fibrinogen, plasma zinc and copper, and a decrease in plasma iron. Changes in these proteins and elements are mediated by the liver following neural input that arises in the hypothalamus. These changes are geared to reallocate energy resources to the generation of fever and the proliferation of immune cells and to induce as hostile an environment to invading pathogens as possible. There are four primary cytokine mediators of this response.

Interleukin-1 β (IL-1 β ) is the chief mediator of the acute phase response following infection. There are two additional members of the IL-1 family, IL-1a and IL-1 receptor antagonist, but neither of these have any effect in producing the acute phase response. IL-1 β exerts its effects within the CNS by induction of the enzyme cyclo-oxygenase type 2 (COX2) in endothelial cells of the vasculature at the circumventricular organs, especially the organum vasculosum of the lamina terminals (Figure 2.9). Induction of this enzyme results in the generation of prostaglandin E2 (PGE2) that passes through the fenestrated blood brain barrier and binds to the type 4 prostanoid receptor (EP4). Receptor binding raises cyclic adenosine monophosphate (cAMP) in neurons of the hypothalamus and brainstem, most notably the preoptic anterior, paraventricular, and A2 nuclei, which induces fever, activates the neuroendocrine axis and stimulates hepatic acute phase protein synthesis and release. An alternate mechanism that may contribute to other aspects of sickness behavior is the binding of IL-1 β to the receptors on the subdiaphragmatic vagus.
Projections from the nucleus tractus solitarius to the hypothalamus, hippocampus, amygdala and other limbic sites are proposed to induce somnolence, anorexia, irritability and cognitive impairment. This pathway and the central release of PGE2 has also been suggested to induce the mirror-like CNS generation of cytokines that is observed with activation of the immune system. The CNS sources of cytokines, such as IL-1 β , interferons, and TNF are from activated astrocytes, lie in the figure at right, as well as from microglia and neurons.
Interleukin-6 does not induce the acute phase response when injected alone, yet nevertheless is the most potent agent for prolonged induction of acute phase proteins when injected to the brain of animals already primed by interleukin-1. Most likely these effects are because IL-6 receptor (IL-6R) is expressed at low levels in non-primed animals, but the receptor is up-regulated during induction of sickness responses. Thus, it has been proposed that IL-6 functions to sustain the acute phase response that is triggered by IL-1 β . Activation of the neuroendocrine axis by IL-1ß and IL-6 results in elevated plasma cortisol that in turn suppresses COX2 and IL-6R expression. This feedback is essential for termination of the acute phase response as the illness resolves.
The interferons (type I) and tumor necrosis factor. These agents are much less potent than those above, yet play especially prevalent roles in the sickness responses with viral and neoplastic illnesses.
Other hormones produced by lymphoid cells include a whole constellation we have already discussed including GH, Prolactin, ACTH, TSH, β -endorphin and enkephalins that may also be involved in the signal pathways between the immune system and the CNS.

Psychoneuroimmunology refers to the pathways that underlie brain-induced modifications of immune system function. These pathways include the neuroendocrine system as well as inputs to all lymphoid tissues from the sympathetic and parasympathetic nervous systems. Immunological responses can be conditioned like any other biological response and so, components of many common diseases ranging from asthma to cancer have been correlated to various behavioral traits.

Secretion of the posterior pituitary hormones is directly from magnocellular neurons of the paraventricular and supraoptic nuclei into the circulation. These neurons project axons into the posterior pituitary via the hypothalamo-neurohypophyseal tract and terminate on a capillary bed of the inferior hypophyseal artery. Control of release in this system is under neural control and so this represents a reflex system with neural input and hormonal output.

Secretion of anterior pituitary hormones is driven by the influence of releasing, or release-inhibiting hormones (factors) that are synthesized in parvocellular neurons of the supraoptic, paraventricular, arcuate and periventricular hypothalamic nuclei. These neurons project axons in the tuberoinfundibular tract onto a capillary bed of the superior hypophyseal artery at the base of the median eminence. These capillaries coalesce into the hypophyseal portal veins, which descend to the anterior pituitary and form a second capillary bed where the anterior pituitary hormones are released. The anterior pituitary hormones diffuse to peripheral targets to provoke release of endocrine hormones that induced tissue effects. Control of release in this system is via feedback of releasing-hormones, anterior pituitary hormones, and peripheral endocrine hormones onto hypothalamic and pituitary cells in a series of feedback loops. This system thus represents a hormone-and neural-evoked and hormone-output reflex.

The immune system provokes neural and neuroendocrine responses in an acute phase “sickness” response to illness or injury. The immune system is also influenced by neural activity.