Structure and Function of and Hypothalamic nuclei

1. Definition and localization The hypothalamus is a small, central region of the formed by nervous fibers and a conglomerate of nuclear bodies with various functions. The hypothalamus is considered to be a link structure between the nervous and the endocrine system, its main function being to maintain the homeostasis of the body. The hypothalamus is located under the from which it is separated by the hypothalamic sulcus of Monro. The sulcus is located at the lateral wall of the and extends anteroposteriorly from the interventricular foramen of Monro (that assures the communication between the third, diencephalic ventricle and the frontal horn of each lateral ventricle) up to the level of Sylvius . The hypothalamus is limited anteriorly by the lamina terminalis, a gray matter layer of triangular aspect extended above the chiasma optique, in between the two anterior horns of the fornix. Lamina terminalis also forms the anterior wall of the third ventricle and contains the organum vasculosum, a circumventricular structure characterized by the absence of blood–brain barrier and thus highly sensitive to osmotic variations of the blood. The superior wall of the hypothalamic region participates in the formation of the inferolateral wall of the third ventricle of the brain and has close relations with the white matter structure that surrounds it, called the fornix. The fornix is a C-shaped white cerebral structure that connects various parts from the brain (hypothalamic nuclei with hippocampal region, thalamic nuclei with hypothalamus’s mammillary bodies). Even if its function is not clearly understood, its relation with memory is known, and recent studies are testing its deep brain stimulation as a treatment in advanced Alzheimer’s disease. Posteriorly, the hypothalamus extends up to the periaqueductal gray substance and the tegmentum of the superior part of the brainstem. Only on the inferior surface of the brain, the hypothalamus can be visualized from the optic chiasm and the anterior perforated substance anteriorly to the posterior cerebral peduncles of the midbrain and the mammillary bodies, dorsally (Figure 1). The mammillary bodies are small, round white-matter structures that belong to the limbic system. They are involved in memory due to their connections with the hippocampal region and also in maintaining the sense of direction. The hypothalamus is limited laterally by the optic tracts in their direction toward the lateral geniculate bodies, an important relay of the optical pathway. Inside the delimited area on the exterior surface of the brain, a small prominence, called tuber cinereum or infundibulum connects the hypothalamus with the posterior lobe of the underneath pituitary gland. The pituitary or the hypophyseal gland is located at the base of the brain, in a depression of the sphenoid bone called the sella turcica.

2. Structure of the hypothalamus: The hypothalamus is a divided into 3 regions (supraoptic, tuberal, mammillary) in a parasagittal plane, indicating location anterior-posterior; and 3 areas (periventricular, medial, lateral) in the coronal plane, indicating location medial-lateral. Hypothalamic nuclei are located within these specific regions and areas. It is found in all vertebrate nervous systems. In mammals, magnocellular neurosecretory cells in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus produce neurohypophysial hormones, oxytocin and vasopressin. These hormones are released into the blood in the posterior pituitary. Much smaller parvocellular neurosecretory cells, neurons of the paraventricular nucleus,

release corticotropin-releasing hormone and other hormones into the hypophyseal portal system, where these hormones diffuse to the anterior pituitary. Supraoptic Region. In the supraoptic region (above the optic chiasm) there are a number of named nuclei, the most prominent being the supraoptic and paraventricular. Neither of these two nuclei is large, but each is easily recognized because it is made up of relatively large, deeply staining cells. The cells in these two nuclei secrete vasopressin (ADH, antidiuretic hormone), oxytocin, and CRH (corticotropin releasing hormone). ADH and oxytocin are transported down the axons from cells in the supraoptic and paraventricular nuclei through the infundibulum to the neurohypophysis (posterior pituitary), where they are released into the blood stream (Fig. 3A). This pathway is termed the supraopticohypophysial tract. Damage to the anterior hypothalamus blocks the production of ADH, resulting in diabetes insipidus, which is characterized by rapid water loss from the kidneys. CRH is released by the paraventricular and taken up by the portal system where it has its action on the anterior lobe of the pituitary. A recent, interesting development is the finding of a direct projection from the eye to the suprachiasmatic nucleus of the supraoptic hypothalamic region. The hypothalamus is thought to contain the “biological clock” that regulates certain body functions that vary at different times of the day (e.g., body temperature, hormone secretion, hunger) or those that vary over a period of many days (e.g., menstrual cycle). This projection from the retina to the suprachiasmatic nucleus is thought to supply the clock with day-night information needed for synchronizing diurnal (daily) rhythms (also known as circadian rhythms). Lesions of the hypothalamus often disrupt the state of the sleep-waking cycle.

Tuberal Region: The tuberal region (at the level of the tuber cinereum) is commonly divided into medial and lateral parts by a plane passing through the fornix. The fornix is a fiber tract that originates in the hippocampus within the temporal lobe and courses rostrally along a Cshaped course next to the lateral ventricle, then plunges into the hypothalamus where it terminates within the mammillary bodies. The medial part of the tuberal region (between the fornix and third ventricle) contains 2 important nuclei; the lateral part, which is more loosely organized, is termed the lateral hypothalamic area (LHA). The medial bundle, which is described below, courses through the LHA. The largest and most prominent of the nuclei in the medial part of the tuberal region is the ventromedial nucleus. One important function that has been attributed to the ventromedial nucleus is control of eating. Bilateral lesions of the ventromedial nucleus in animals and probably humans as well, result in overeating (hyperphagia) and extreme obesity as well as a chronically irritable mood and increase in aggressive behavior (termed hypothalamic rage). By contrast, bilateral lesions in the lateral hypothalamic area result in anorexia (lack of appetite). Animals with lesions in this area may die of starvation. As a result of these lesion studies (along with supporting stimulation studies), the ventromedial nucleus has been referred to as a satiety center and the lateral hypothalamic area as a feeding center. It has been postulated that these opposing centers define a “set point” for body weight: the set point theory of weight control. According to this theory, when body weight goes below the set point, the lateral hypothalamus is activated and appetite is increased; when body weight goes above the set point, the ventromedial nucleus is activated and appetite is decreased. This theory was questioned in the past, but recent evidence has been obtained that supports an integrative role of the ventromedial nucleus and lateral hypothalamic area in body weight control: their neurons respond to glucose, free fatty acid and insulin levels in a manner consistent with the set point theory, and activity levels in the two nuclei display a strict reciprocal relationship that is appropriately correlated with the level of hunger or satiety. A second nucleus of great importance in the tuberal region is the arcuate nucleus (also known as the infundibular or periventricular nucleus). This nucleus apparently contains many of the neurons that control the endocrine functions of the adenohypophysis (although cells with this role are also found in other nuclei of the tuberal region as well as in the supraoptic region and preoptic area). These neurons do not directly release hormones from their endings like neurons in the supraoptic region, but rather secrete releasing or release-inhibiting factors (also termed releasing hormones) that regulate release of hormones by the

adenohypophysis. Releasing factors are secreted from terminals of these neurons in the median eminence and infundibulum where they enter the portal system of vessels which carries them into the adenohypophysis. Hormones under control of this system include: growth hormone, ACTH, thyrotropin, the gonadotropins (FSH and LH), and prolactin. Consideration of the functional roles of these hormones is beyond the scope of this course.

Mammillary Region: Mammillary Region The mammillary part of the hypothalamus consists of the posterior hypothalamic nucleus and the prominent mammillary nuclei. The posterior nucleus is a large, ill- defined group of cells that may play a role in thermoregulation. The mammillary nuclei are considered to be part of the hypothalamus on anatomical grounds, but, unlike the other hypothalamic nuclei, they do not appear to be closely related to autonomic and endocrine functions. Instead, the mammillary nuclei are believed to play a role in memory.

Cross section through mammillary region

3. Connections of the hypothalamus: Hypothalamus communicates with the rest of the body via three routes:  Bloodstream or Endocrine connections  Nervous connections  Nervous connections The nervous connections can be divided into afferent and efferent fibers. Afferent fibers Hypothalamus receives afferent fibers carrying somatic and visceral sensations as well as from special senses. Following are the important afferents of hypothalamus:  Somatic and visceral afferents via lemniscal afferent fibers and nucleus of tractus solitarius, that reach the hypothalamus via reticular formation  Visual afferents from the optic chiasma reach the suprachiasmatic nucleus  Olfactory afferents are received through medial forebrain bundle  Auditory afferents though not identified completely but are influenced by the hypothalamus  Hippocampo-hypothalamic afferents reach via fornix to mamillary bodies  Tegmental fibers from midbrain  Thalamo-hypothalamic fibers from the midline and dorsomedial nuclei of the thalamus  Amygdalo-hypothalamic fibers from the amygdaloid complex reach the hypothalamus via Efferent fibers : The efferent connections of hypothalamic nuclei are also complex and numerous. Here, we will mention some important connections.  To brain stem and spinal cord: The hypothalamic nuclei send efferent fibers to nuclei present in the brainstem and spinal cord. In this way, they control the autonomic nervous system.

 Mammillothalamic Tract: This tract consists of fibers arising in the mamillary body and terminating in the anterior nucleus of thalamus.  Mammillotegmental Tract: These fibers terminate in the reticular formation, present in the tegmentum of the midbrain.  Limbic System: The nuclei in the hypothalamus also send efferent fibers to the various nuclei of the limbic system.

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Endocrine Connections Hypothalamus uses the bloodstream to communicate with the pituitary gland. These connections of the hypothalamus are called the bloodstream or endocrine connections. The cells of the pituitary gland release hormones in response to the regulating factors or hormones released by the hypothalamus. These regulatory factors reach the pituitary gland via the hypophyseal portal system of veins. Hypothalamus also uses nervous connections to communicate with the pituitary gland. The cell bodies of these neurons are present in the hypothalamus and the axonal terminals in the posterior pituitary gland. These neurons synthesize the oxytocin and vasopressin hormones, which are stored in the axonal terminals in the posterior pituitary and are released on demand. So, hypothalamus communicates with the anterior pituitary (Adenohypophysis) by hypothalamo- hypophysial portal system. Secretion of anterior pituitary is controlled by either hypothalamic releasing or hypothalamic inhibitory hormones or factors which were secreted within hypothalamus and communicate with anterior pituitary though hypothalamo-hypophysial portal system. On the other hand secretion from the posterior pituitary is controlled by the nerve signals that originates in hypothalamus and terminate to posterior pituitary via neurosecretory tract. Blood Supply of Hypothalamus Hypothalamus receives blood mainly from the hypophyseal artery, a branch of the anterior cerebral artery. All the blood from the hypothalamus is drained into the hypothalamohypophyseal system of veins and distributed to the pituitary gland. From the pituitary gland, the blood is drained via the hypophyseal vein. Other Connection: The hypothalamus is a small region of the brain connected with numerous, various cerebral structures that allows it to intervene in many regulatory processes of the organism. It has an important role in the optimal, normal functioning of the body, and it controls the endocrine system, the metabolism, and it is involved in stress control and in other different actions that modulates a person’s behavior. More, the hypothalamus is involved in the homeostasis of the organism in terms of body temperature, blood pressure, fluid balance, and body weight. The connections of the hypothalamus are made with the following structures.  The midbrain The ascending reticular activating system represents a structure composed by neural fibers passing from the reticular formation of the midbrain, through the thalamus, reaching the cerebral cortex. The system is responsible for concentration, attention, and for maintaining the awakening state. Through it, the reticular formation is connected with the hypothalamic nuclei: the lateral mammillary bodies, the tuberomammillar nuclei, and the periventricular ones. The periventricular nuclei receive information about the general visceral sensibility while the two others mediate behavior and are involved in consciousness. Information from the solitary tract nucleus passing from the reticular substance of the midbrain can also reach the hypothalamus. The nucleus of the solitary tract is connected with the hypothalamus through either the solitarohypothalamic tract or through colaterales from the solitariothalamic tract.  The thalamus The anterior hypothalamus has connections with the intralaminar nucleus and the nucleus of the median line. Recent studies described that lesions of the intraluminal group of nucleus can lead to Parkinson’s disease or even schizophrenia. The mammillothalamic fascicle of Vicq d’Azyr connects both the medial and lateral mammillary nuclei with the anterior part of the thalamus; its destruction in case of a cerebral hemorrhage is associated withmemory loss.  The amygdala The amygdala represents a conglomerate of perykarions located in the temporal lobe. Efferent fibers from this region project directly to hypothalamus or neural fibers can detach from the amygdala-thalamic fascicle and reach the anterior hypothalamus. It is involved in body’s response to fear and rewards but also in memory. Direct connections of amygdala with the hypothalamus are either through the ventral amygdalofugal pathway or through the stria terminalis.  The hippocampal region The hippocampus is a curved-shaped cerebral structure located in the temporal lobe. It is formed by the dentate gyrus and different regions called Cornus Ammonis (CA): CA1, CA2, CA3, and CA4 . CA1 and CA3 are connected with the infundibular and the ventromedial nuclei of the hypothalamus. According to a recent study CA2 area lighted that also CA2 area, a small region in the hippocampus composed from pyramidal neurons, is involved in memory and learning through its connections with the supramammillary nuclei of the hypothalamus.

 The olfactory bulb Fibers from the olfactory bulb reach the periamigdalian region (the entorhinal and periamygdaloid cortex) and then the lateral hypothalamus through either the amigdalian or the accumbens nucleus.  The retina Visual information from the retinal neuroepithelium through the lateral geniculate body of the mesencephalon and then the superior colliculus reach the suprachiasmatic and supraoptic nuclei of the hypothalamus and are involved in circadian rhythm. The hypothalamus can receive direct fibers from the retina through a retinohypothalamic tract that reach the suprachiasmatic nuclei. The connections are involved in the circadian rhythm.  Cerebral cortex There is a double sense connection between the cerebral cortex and the hypothalamus. The hypothalamus projects on the surface of the cortex diffuse, in a poorly defined area over the cortex and transmits information that maintain the cortical tonus while from the gray matter of the cerebral cortex, neural fibers projects over the hypothalamus and triggers visceral response according to the affective state (sweating in case of fear, intestinal manifestations in case of stress). Neural fibers from the lateral hypothalamus project in the prefrontal cortex while the frontal lobe also has efferent for all the hypothalamic regions. Through these connections, the autonomic control is assured in the organism. More, from the paraorbital gyrus, fibers project into the paraventricular and ventromedial nuclei. Axons from the spinal cord can project in the hypothalamic region using the path of the spinohypothalamic tract. They carry out pain and temperature information. The hypothalamus exerts its effects within two projections: the spinothalamic tract reaching the lateral horn of the spinal cord of T1-L2 segments regulates the sympathetic autonomic response; the mammillotegmental tract and the dorsal longitudinal fasciculus carry out information from the posterior region of the hypothalamus while the anterior one connects with the thalamus (mammillothalamic tract) and the above fornix. Functions of the hypothalamus The hypothalamus is involved in different daily activities like eating or drinking, in the control of the body’s temperature and energy maintenance, and in the process of memorizing and in stress control. It also modulates the endocrine system through its connections with the pituitary gland.  Thermoregulation Thermoregulation is the process that allows maintenance of the body’s temperature within normal ranges. In case of high body temperature, the hypothalamus responds through thermoregulatory heat loss behavior (either sweating or vasodilatation). If the body needs to be warm up, hypothalamus can determine heat production behavior (vasoconstriction, thermogenesis—heat production from muscles, brain or other organs, including the thyroid gland).They are of the hypothalamus responsible for controlling this process is the anterior one, more specific the preoptic nucleus.  Regulation of food intake The hypothalamus controls appetite and food intake through the ventromedial, dorsomedial, paraventricular, and lateral hypothalamus nucleus. The ventromedial nucleus is referred to as the appetite-suppressing or anorexigenic center. Destruction of this nucleus leads to hyperpolyphagia, obesity, and to an aggressive behavior. Contrary, the appetite-increasing or orexigenic center is considered to be the lateral hypothalamic nucleus that can lead to aphagia and cashexy in case of its destruction and to hyperphagia or polyphagia in case of its stimulation. Appetite control is modulated by the leptin hormone released by the fatty cells that binds to specific hypothalamic receptors.  Regulation of body water content Water control in the living organism is assured by the hypothalamus through the antidiuretichormone (ADH) secretion. In cases of blood volume loss and dehydration, the ADH hormone is secreted from the supraoptic nucleus–that have osmoreceptor cells–and released in the circulation. The peptide is directed toward the specific receptor from kidneys and decreases the urine production with subsequent water retention in the organism.  Center for autonomic nervous system The hypothalamus regulates both sympathetic and parasympathetic systems. The anterior region of the thalamus has an excitatory effect over the sympathetic system while the posterior and lateral ones have an excitatory effect over the parasympathetic system.  Endocrine control The endocrine control is realized through the pituitary gland or the hypophysis situated below the tuberal region of the hypothalamus. The hypothalamus is connected with the posterior lobe of the gland through the

hypothalamo-hypophyseal tract. Along these fibers, the AHD and oxytocin hormones are transported into the neurohypophysis where they are stocked in vesicles. Hormones secretion in the body is regulated by the hypothalamus through the releasing and inhibitor factors: thyrotropin-releasing, gonadotropin-releasing, corticotrophin-releasing, somatostatin, and dopamine. These hormones are involved in the process of growth, in the reproduction, in the metabolism of the body, and also can assure the homeostasis of the body.

 Reproduction The reproduction function of an organism is assured by the hypothalamic-pituitary-gonadal axis. The gonadotropin-realizing hormone (GnRH) secreted by the hypothalamus stimulates the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the anterior subdivision of the pituitary gland. Action of these two hormones on the gonads determines the estrogen and testosterone production. Behavior in males and females is influenced as well by the sex steroids. The neurons in the preoptic are involved in the male sexual behavior while the ones from the tuberal regional exert their properties in females.  The circadian rhythm The photosensible suprachiasmatic nucleus is involved, along with is connections with the pituitary gland, in the circadian rhythm. The suprachiasmatic nucleus receives electro-chemical information from the stimulated retina. The circadian rhythm represents the endogenous clock of an organism that is involved in the well-being of the body due to keeping within normal limits the major functions. Despite its reduced size, the hypothalamus represents an important, integrative region of the brain with complex functions and multiple connections with essential cerebral structures. Hypothalamic Nuclei: Within hypothalamus, huge clusters of neurosecretory cells present called hypothalamic nuclei which are located around the third ventricle. The hypothalamus houses multiple nuclei along with afferent and efferent nerve fibers that connect the hypothalamus to the various portions of the brain and brainstem. It is divided into four regions: from anterior to posterior, the preoptic, supraoptic, tuberal, and mamillary regions; and three zones: laterally from the third ventricle, the periventricular, medial, and lateral 4 zones.

Schematic representation of lateral brain section demonstrating hypothalamic nuclei. Dashed lines represent the frontal (coronal) 1, preoptic nucleus; 2, paraventricular nucleus; 3, anterior hypothalamic areas; 4, supraoptic nucleus; 5, arcuate nucleus; 6, dorsal hypothalamic area; 7, dorsomedial nucleus; 8, ventromedial nucleus; 9, posterior hypothalamic area; 10, mamillary body; 11, optic chiasm; 12, optic nerve. (From Braunstein GD: The hypothalamus. In Melmed S [ed]: The Pituitary, 2nd ed. Cambridge, MA: Blackwell Scientific, 2002, pp 317–348.)

The hypothalamic nuclei include the following:

List of nuclei, their functions, and the neurotransmitters, neuropeptides, or hormones that they utilize

Region Area Nucleus Function[9]

Preoptic Preoptic nucleus  Thermoregulation

 Regulates the release of gonadotropic hormones from the adenohypophysis  Contains the sexually dimorphic nucleus, which releases GnRH, Medial preoptic nucleus differential development between sexes is based upon in utero testosterone levels  Thermoregulation[10]

 Vasopressin release

Supraoptic nucleus  Oxytocin release

 thyrotropin-releasing hormone release Anterior Medial  corticotropin-releasing hormone release (supraoptic) Paraventricular nucleus  oxytocin release  vasopressin release  somatostatin release

 thermoregulation Anterior hypothalamic  panting

nucleus  sweating  thyrotropin inhibition

Suprachiasmatic nucleus  Circadian rhythms

Lateral See Lateral hypothalamus § Function – primary source of orexin neurons Lateral nucleus that project throughout the brain and spinal cord

 blood pressure Dorsomedial hypothalamic  heart rate nucleus  GI stimulation

 satiety

Medial Ventromedial nucleus  neuroendocrine control Middle (tuberal)  Growth hormone-releasing hormone (GHRH)

Arcuate nucleus  feeding  Dopamine-mediated prolactin inhibition See Lateral hypothalamus § Function – primary source of orexin neurons

Lateral nucleus Lateral that project throughout the brain and spinal cord

Lateral tuberal nuclei Mammillary nuclei (part of mammillary bodies)  memory

Increase blood pressure Medial   pupillary dilation Posterior nucleus  shivering  vasopressin release Posterior See Lateral hypothalamus § Function – primary source of orexin neurons

(mammillary) Lateral nucleus that project throughout the brain and spinal cord

 arousal (wakefulness and attention) Lateral  feeding and energy balance Tuberomammillary [11]  learning nucleus  memory  sleep

Regulation of Neuroendocrine gland

The hypothalamus, located at the most rostral region of the brainstem in the diencephalon, is a key center regulating numerous and diverse physiological functions, including growth, metabolism, stress responses, repro- duction, osmoregulation, and circadian rhythms. All these functions are critically involved in maintaining the homeostasis of the organism and in coordinating the occurrence and timing of physiological functions with the appropriate environmental conditions. In order to accomplish this, the hypothalamus acts as an integrator, receiving converging inputs from the sensory and auto- nomic systems related to the internal and external environment of the organism. The hypothalamus responds rapidly to this convergent information by changing its output of neurotransmitters and neuropeptides, which in turn effect change at its targets within the central nervous system (CNS), the pituitary gland, and the blood- stream. The hypothalamus contains several populations of cells that are define as neuroendocrine, meaning that they have both neuronal and endocrine features. The neuroendocrine cells express neural markers and release a peptide or neurotransmitter in response to a depolarizing stimulus, similar to other neurons in the brain. Unlike other “traditional” neurons, neuroendocrine cells release their neurotransmitter directly into a blood system. Considering that endocrine glands are defined by the release of a chemical into the bloodstream, neuroendocrine cells are part of the endocrine system. Although the chemicals released by most neuroendocrine cells are peptides and neurotransmitters, they are also appropriately referred to as hormones, or neurohormones, because of this endocrine property. The primary target of hypothalamic neuroendocrine cells is the pituitary gland, comprising the anterior pituitary (adenohypophysis) and the posterior pituitary (neurohypophysis). Some species also possess an intermediate pituitary lobe. Hypothalamus communicates with the anterior pituitary (Adenohypophysis) by hypothalamo-hypophysial portal system. Secretion of anterior pituitary is controlled by either hypothalamic releasing or hypothalamic inhibitory hormones or factors which were secreted within hypothalamus and communicate with anterior pituitary though hypothalamo-hypophysial portal system. On the other hand secretion from the posterior pituitary is controlled by the nerve signals that originates in hypothalamus and terminate to posterior pituitary via neurosecretory tract.

HYPOTHALAMIC CONTROL OF ANTERIOR PITUITARY HORMONES AND THEIR REGULATED FUNCTIONS:

The hypothalamic regulation of anterior pituitary hormonal synthesis and release is integral to the regulation of stress, reproduction, metabolism, growth, and lactation. With the exception of the prolactin-inhibiting hormone (dopamine), all of the hypothalamic releasing/inhibiting hormones are peptides that are cleaved from larger prohormones. The pituitary hormones are all large peptides or small proteins. Pituitary hormone release into the general circulation is stimulated by hypothalamic releasing hormones, and each pituitary hormone targets a tertiary organ to cause hormone release or a functional outcome. In the case of hypothalamic inhibiting hormones, pituitary hormone synthesis/ secretion is inhibited. Reproductive and stress axes regulate each other at specific hypothalamic neurons, both through direct actions at the CNS, as well as through feedback from the target steroid hormones.

Fig. Model for regulation of anterior pituitary hormone secretion by three tiers of control.

 Hypothalamic Control of Stress: Overview, Characteristics and Physiological Functions of the Hypothalamic-Pituitary-Adrenal Axis

Hypothalamic Control of Basal Metabolism: Overview, Characteristics, and Physiological Functions of the Hypothalamic-Pituitary-Thyroid Axis.

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Hypothalamic Control of Growth: Overview, Characteristics, and Physiological Functions of the Hypothalamic-Somatotropic Axis.

Hypothalamic Control of Reproduction: Overview, Characteristics, and Physiological Function of the Hypothalamic-Pituitary-Gonadal Axis:

Hypothalamic Control of Lactation: Overview, Characteristics, and Physiology of the Hypothalamic- Lactational Axis:

HYPOTHALAMIC CONTROL OF POSTERIOR PITUITARY HORMONES AND THEIR REGULATED FUNCTIONS: The posterior pituitary releases two major neurohormones, oxytocin and vasopressin (referred to here as arginine vasopressin or AVP; also called anti-diuretic hormone or ADH). The hypothalamic- neurohypophysial AVP and oxytocin neurons have large cell somata that are 20–40 μm in diameter, and are referred to as magnocellular neurons(as opposed to their parvo- cellular counterparts of 10–15 μm. These cells are localized in the supraoptic nucleus (SON), comprised entirely of magnocellular neurons; and the paraventricular nucleus (PVN), which has both magnocellular and parvocellular divisions. The hypothalamic-neurohypophysial somata in the SON and PVN project axons that traverse the pitui- tary stalk and terminate in the posterior pituitary gland. These axon terminals are abundant in secretory granules storing oxytocin or AVP, and in response to depolarization of their cell bodies, release these neuropep- tides into general circulation.

FEEDBACK MECHANISM:

Feed Back Control: The process of inhibiting of stimulating the first step by the final step in a hormonal reaction pathway, is called feedback regulation. The secretion of a hormone may be stimulated or inhibited by the feedback effect of some other hormone or metabolite. This feed back control can be divided into two ways- (a).Negative feedback mechanism: In this type, rising concentration of a hormone inhibits the release of second hormone from other gland, called negative feedback control (fig. 3.2). The negative feed back loops that govern the hypothalamic-pituitary axis include Long loop feedback: hormones from peripheral endocrine glands can exert feedback control on the hypothalamus and anterior pituitary. This feedback is usually negative. Short-loop feedback: Negative feedback by pituitary hormones can inhibit the synthesis and/or secretion of the related hypothalamic hormones. Ultra-short loop feedback: Ultrashort feedback mechanisms are endocrine control loops where a hormone directly inhibits its own secretion via paracrine or autocrine effects. Characteristically, regulation is maintained without the intermediate step of an additional hormone.

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This is even evidence that secreted hypophysial hormones may feedback on their cells of origin to inhibit their own secretion, referred as autoinhibition. Feedback loops are important because they allow living organisms to maintain homeostasis. Homeostasis is the mechanism that enables us to keep our internal environment relatively constant – not too hot, or too cold, not too hungry or tired. The level of energy that an organism needs to maintain homeostasis depends on the type of organism, as well as the environment it inhabits. Cyclic changes: The above-mentioned regulations follow other influences as well, which can be summarized as “cyclic changes of secretion of hormones”. We can include here the effect of sleep, changing of the seasons of the year and our development and aging. These changes are usually based on the activity of the central nervous system pathways that change over time of day, cycle sleep/vigil and throughout the year. A good example is the secretion of growth hormone, which reaches its peak during the early stages of sleep, but as sleep progresses it returns again to a maintenance level.

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Cyclic changes Short loop and long loop feedback

PITUITARY GLAND HORMONES AND THEIR FUNCTIONS

Pituitary gland, also called hypophysis, ductless gland of the endocrine system that secretes hormones directly into the bloodstream. The term hypophysis (from the Greek for “lying under”)— another name for the pituitary—refers to the gland’s position on the underside of the brain. The pituitary gland is called the “master gland” because its hormones regulate other important endocrine glands— including the adrenal, thyroid, and reproductive glands (e.g., ovaries and testes)—and in some cases have direct regulatory effects in major tissues, such as those of the musculoskeletal system. The pituitary gland lies at the middle of the base of the skull and is housed within a bony structure called the sella turcica, which is behind the nose and immediately beneath the hypothalamus. The pituitary gland is attached to the hypothalamus by a stalk composed of neuronal axons and the so-called hypophyseal-portal veins. Its weight in normal adult humans ranges from about 500 to 900 mg (0.02 to 0.03 ounce). In most species the pituitary gland is divided into three lobes: the anterior lobe, the intermediate lobe, and the posterior lobe (also called the neurohypophysis or pars nervosa). In humans the intermediate lobe does not exist as a distinct anatomic structure but rather remains only as cells dispersed within the anterior lobe. Nonetheless, the anterior and posterior lobes of the pituitary are functionally, anatomically, and embryologically distinct. Whereas the anterior pituitary contains abundant hormone-secreting epithelial cells, the posterior pituitary is composed largely of unmyelinated (lacking a sheath of fatty insulation) secretory neurons.

Fig. The anatomy of the mammalian pituitary gland, showing the anterior lobe (adenohypophysis), the posterior lobe (neurohypophysis), the paraventricular and supraoptic nuclei, and other major structures and blood supplies.

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Posterior Pituitary The posterior pituitary is actually an extension of the neurons of the paraventricular and supraoptic nuclei of the hypothalamus. The cell bodies of these regions rest in the hypothalamus, but their axons descend as the hypothalamic–hypophyseal tract within the infundibulum, and end in axon terminals that comprise the posterior pituitary.

Figure. Neurosecretory cells in the hypothalamus release oxytocin (OT) or ADH into the posterior lobe of the pituitary gland. These hormones are stored or released into the blood via the capillary plexus.

The posterior pituitary gland does not produce hormones, but rather stores and secretes hormones produced by the hypothalamus. The paraventricular nuclei produce the hormone oxytocin, whereas the supraoptic nuclei produce ADH. These hormones travel along the axons into storage sites in the axon terminals of the posterior pituitary. In response to signals from the same hypothalamic neurons, the hormones are released from the axon terminals into the bloodstream. Oxytocin When fetal development is complete, the peptide-derived hormone oxytocin (tocia- = “childbirth”) stimulates uterine contractions and dilation of the cervix. Throughout most of pregnancy, oxytocin hormone

receptors are not expressed at high levels in the uterus. Toward the end of pregnancy, the synthesis of oxytocin receptors in the uterus increases, and the smooth muscle cells of the uterus become more sensitive to its effects. Oxytocin is continually released throughout childbirth through a positive feedback mechanism. As noted earlier, oxytocin prompts uterine contractions that push the fetal head toward the cervix. In response, cervical stretching stimulates additional oxytocin to be synthesized by the hypothalamus and released from the pituitary. This increases the intensity and effectiveness of uterine contractions and prompts additional dilation of the cervix. The feedback loop continues until birth. Although the mother’s high blood levels of oxytocin begin to decrease immediately following birth, oxytocin continues to play a role in maternal and newborn health. First, oxytocin is necessary for the milk ejection reflex (commonly referred to as “let-down”) in breastfeeding women. As the newborn begins suckling, sensory receptors in the nipples transmit signals to the hypothalamus. In response, oxytocin is secreted and released into the bloodstream. Within seconds, cells in the mother’s milk ducts contract, ejecting milk into the infant’s mouth. Secondly, in both males and females, oxytocin is thought to contribute to parent–newborn bonding, known as attachment. Oxytocin is also thought to be involved in feelings of love and closeness, as well as in the sexual response. Antidiuretic Hormone (ADH) The solute concentration of the blood, or blood osmolarity, may change in response to the consumption of certain foods and fluids, as well as in response to disease, injury, medications, or other factors. Blood osmolarity is constantly monitored by osmoreceptors—specialized cells within the hypothalamus that are particularly sensitive to the concentration of sodium ions and other solutes. In response to high blood osmolarity, which can occur during dehydration or following a very salty meal, the osmoreceptors signal the posterior pituitary to release antidiuretic hormone (ADH). The target cells of ADH are located in the tubular cells of the kidneys. Its effect is to increase epithelial permeability to water, allowing increased water reabsorption. The more water reabsorbed from the filtrate, the greater the amount of water that is returned to the blood and the less that is excreted in the urine. A greater concentration of water results in a reduced concentration of solutes. ADH is also known as vasopressin because, in very high concentrations, it causes constriction of blood vessels, which increases blood pressure by increasing peripheral resistance. The release of ADH is controlled by a negative feedback loop. As blood osmolarity decreases, the hypothalamic osmoreceptors sense the change and prompt a corresponding decrease in the secretion of ADH. As a result, less water is reabsorbed from the urine filtrate. Interestingly, drugs can affect the secretion of ADH. For example, alcohol consumption inhibits the release of ADH, resulting in increased urine production that can eventually lead to dehydration and a hangover. A disease called diabetes insipidus is characterized by chronic underproduction of ADH that causes chronic dehydration. Because little ADH is produced and secreted, not enough water is reabsorbed by the kidneys. Although patients feel thirsty, and increase their fluid consumption, this doesn’t effectively decrease the solute concentration in their blood because ADH levels are not high enough to trigger water reabsorption in the kidneys. Electrolyte imbalances can occur in severe cases of diabetes insipidus. Anterior Pituitary The anterior pituitary originates from the digestive tract in the embryo and migrates toward the brain during fetal development. There are three regions: the pars distalis is the most anterior, the pars intermedia is adjacent to the posterior pituitary, and the pars tuberalis is a slender “tube” that wraps the infundibulum. Recall that the posterior pituitary does not synthesize hormones, but merely stores them. In contrast, the anterior pituitary does manufacture hormones. However, the secretion of hormones from the anterior pituitary is regulated by two classes of hormones. These hormones—secreted by the hypothalamus—are the releasing hormones that stimulate the secretion of hormones from the anterior pituitary and the inhibiting hormones that inhibit secretion. Hypothalamic hormones are secreted by neurons, but enter the anterior pituitary through blood vessels. Within the infundibulum is a bridge of capillaries that connects the hypothalamus to the anterior pituitary.

This network, called the hypophyseal portal system, allows hypothalamic hormones to be transported to the anterior pituitary without first entering the systemic circulation. The system originates from the superior hypophyseal artery, which branches off the carotid arteries and transports blood to the hypothalamus. The branches of the superior hypophyseal artery form the hypophyseal portal system (see Figure 3). Hypothalamic releasing and inhibiting hormones travel through a primary capillary plexus to the portal veins, which carry them into the anterior pituitary. Hormones produced by the anterior pituitary (in response to releasing hormones) enter a secondary capillary plexus, and from there drain into the circulation.

Figure. The anterior pituitary manufactures seven hormones. The hypothalamus produces separate hormones that stimulate or inhibit hormone production in the anterior pituitary. Hormones from the hypothalamus reach the anterior pituitary via the hypophyseal portal system. The anterior pituitary produces seven hormones. These are the growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), beta endorphin, and prolactin. Of the hormones of the anterior pituitary, TSH, ACTH, FSH, and LH are collectively referred to as tropic hormones (trope- = “turning”) because they turn on or off the function of other endocrine glands. Growth Hormone

The endocrine system regulates the growth of the human body, protein synthesis, and cellular replication. A major hormone involved in this process is growth hormone (GH), also called somatotropin—a protein hormone produced and secreted by the anterior pituitary gland. Its primary function is anabolic; it promotes protein synthesis and tissue building through direct and indirect mechanisms. GH levels are controlled by the release of GHRH and GHIH (also known as somatostatin) from the hypothalamus.

Figure. Growth hormone (GH) directly accelerates the rate of protein synthesis in skeletal muscle and bones. Insulin-like growth factor 1 (IGF-1) is activated by growth hormone and indirectly supports the formation of new proteins in muscle cells and bone. A glucose-sparing effect occurs when GH stimulates lipolysis, or the breakdown of adipose tissue, releasing fatty acids into the blood. As a result, many tissues switch from glucose to fatty acids as their main energy source, which means that less glucose is taken up from the bloodstream. GH also initiates the diabetogenic effect in which GH stimulates the liver to break down glycogen to glucose, which is then deposited into the blood. The name “diabetogenic” is derived from the similarity in elevated blood glucose levels observed between individuals with untreated diabetes mellitus and individuals experiencing GH excess. Blood glucose levels rise as the result of a combination of glucose-sparing and diabetogenic effects. GH indirectly mediates growth and protein synthesis by triggering the liver and other tissues to produce a group of proteins called insulin-like growth factors (IGFs). These proteins enhance cellular proliferation and inhibit apoptosis, or programmed cell death. IGFs stimulate cells to increase their uptake of amino acids from the blood for protein synthesis. Skeletal muscle and cartilage cells are particularly sensitive to stimulation from IGFs. Dysfunction of the endocrine system’s control of growth can result in several disorders. For example, gigantism is a disorder in children that is caused by the secretion of abnormally large amounts of GH, resulting in excessive growth. A similar condition in adults is acromegaly, a disorder that results in the growth of bones in the face, hands, and feet in response to excessive levels of GH in individuals who have

stopped growing. Abnormally low levels of GH in children can cause growth impairment—a disorder called pituitary dwarfism (also known as growth hormone deficiency). Thyroid-Stimulating Hormone The activity of the thyroid gland is regulated by thyroid-stimulating hormone (TSH), also called thyrotropin. TSH is released from the anterior pituitary in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. As discussed shortly, it triggers the secretion of thyroid hormones by the thyroid gland. In a classic negative feedback loop, elevated levels of thyroid hormones in the bloodstream then trigger a drop in production of TRH and subsequently TSH. Adrenocorticotropic Hormone The adrenocorticotropic hormone (ACTH), also called corticotropin, stimulates the adrenal cortex (the more superficial “bark” of the adrenal glands) to secrete corticosteroid hormones such as cortisol. ACTH come from a precursor molecule known as pro-opiomelanotropin (POMC) which produces several biologically active molecules when cleaved, including ACTH, melanocyte-stimulating hormone, and the brain opioid peptides known as endorphins. The release of ACTH is regulated by the corticotropin-releasing hormone (CRH) from the hypothalamus in response to normal physiologic rhythms. A variety of stressors can also influence its release, and the role of ACTH in the stress response is discussed later in this chapter. Follicle-Stimulating Hormone and Luteinizing Hormone The endocrine glands secrete a variety of hormones that control the development and regulation of the reproductive system (these glands include the anterior pituitary, the adrenal cortex, and the gonads—the testes in males and the ovaries in females). Much of the development of the reproductive system occurs during puberty and is marked by the development of sex-specific characteristics in both male and female adolescents. Puberty is initiated by gonadotropin-releasing hormone (GnRH), a hormone produced and secreted by the hypothalamus. GnRH stimulates the anterior pituitary to secrete gonadotropins—hormones that regulate the function of the gonads. The levels of GnRH are regulated through a negative feedback loop; high levels of reproductive hormones inhibit the release of GnRH. Throughout life, gonadotropins regulate reproductive function and, in the case of women, the onset and cessation of reproductive capacity. The gonadotropins include two glycoprotein hormones: follicle-stimulating hormone (FSH) stimulates the production and maturation of sex cells, or gametes, including ova in women and sperm in men. FSH also promotes follicular growth; these follicles then release estrogens in the female ovaries. Luteinizing hormone (LH) triggers ovulation in women, as well as the production of estrogens and progesterone by the ovaries. LH stimulates production of testosterone by the male testes.

Prolactin As its name implies, prolactin (PRL) promotes lactation (milk production) in women. During pregnancy, it contributes to development of the mammary glands, and after birth, it stimulates the mammary glands to produce breast milk. However, the effects of prolactin depend heavily upon the permissive effects of estrogens, progesterone, and other hormones. And as noted earlier, the let-down of milk occurs in response to stimulation from oxytocin. In a non-pregnant woman, prolactin secretion is inhibited by prolactin-inhibiting hormone (PIH), which is actually the neurotransmitter dopamine, and is released from neurons in the hypothalamus. Only during pregnancy do prolactin levels rise in response to prolactin-releasing hormone (PRH) from the hypothalamus. Intermediate Pituitary: Melanocyte-Stimulating Hormone The cells in the zone between the pituitary lobes secrete a hormone known as melanocyte-stimulating hormone (MSH) that is formed by cleavage of the pro-opiomelanocortin (POMC) precursor protein. Local production of MSH in the skin is responsible for melanin production in response to UV light exposure. The

role of MSH made by the pituitary is more complicated. For instance, people with lighter skin generally have the same amount of MSH as people with darker skin. Nevertheless, this hormone is capable of darkening of the skin by inducing melanin production in the skin’s melanocytes. Women also show increased MSH production during pregnancy; in combination with estrogens, it can lead to darker skin pigmentation, especially the skin of the areolas and labia minora. Figure 5 is a summary of the pituitary hormones and their principal effects.

DR

Hypopituitarism

With an annual estimated incidence (number of new cases per population in a given time period) of 4.2 per 100,000 and prevalence (proportion of the total number of cases to the total population) of 45.5 per 100,000, hypopituitarism might be caused by either an inability of the gland itself to produce hormones or an insufficient supply of hypothalamic-releasing hormones. It is causally associated with pituitary tumors (61%), non-pituitary lesions (9%), and non-cancerous causes (30%), including perinatal insults, genetic causes, trauma and idiopathic cases. Often, mutations in genes encoding single hormones (or the receptor for their cell-specific hypothalamic releasing factor) result in single pituitary hormone deficiency. Unless successfully treated, hypopituitarism is chronic and lifelong, and in cases of shortage of ACTH or TSH it can cause life threatening events and lead to increased mortality. If there is decreased secretion of most pituitary hormones, the term panhypopituitarism is used.

By: Arturo E. Gonzalez-Iglesias and Richard Bertram

DR SOMATOTROPINOMA This is a tumor of somatotroph cells that represents 15% of pituitary adenomas. The resulting hypersecretion of GH in adults causes acromegaly (an overgrowth of the terminal parts of the

skeleton such as the nose, mandible, hands and feet). When it presents in children and adolescents it causes gigantism; disruption of sexual maturation is common, either because of hormone hypersecretion or because of manifestations caused by compression of hypothalamic connections by the adenoma. NULL CELL ADENOMAS These are dysfunctional tumors that account for 25% of pituitary adenomas. Because they do not secrete hormones, symptoms are restricted to headache, increased intracranial pressure and visual field defects. GONADOTROPHIC ADENOMAS These are tumors of gonadotroph cells that account for 10% of pituitary adenomas. Although functional, they are usually clinically silent. THYROTROPHIC ADENOMAS These are rare (less than 1%) but have the particular characteristic of being plurihormonal, since they produce the common glycoprotein α-subunit, prolactin, and the specific β- subunits of LH and FSH.

HYPOTHALAMO-HYPOPHYSIAL PORTAL SYSTEM

A collection of NEURONS, tracts of NERVE FIBERS, endocrine tissue, and blood vessels in the HYPOTHALAMUS and the PITUITARY GLAND comprise the HYPOTHALAMO-HYPOPHYSIAL PORTAL SYSTEM. This hypothalamo-hypophyseal portal circulation provides the mechanism for hypothalamic neuroendocrine (HYPOTHALAMIC HORMONES) regulation of pituitary function and the release of various PITUITARY HORMONES into the systemic circulation to maintain HOMEOSTASIS. The pituitary gland is a three-lobe structure: anterior, posterior and intermediate lobe, with different embryological origin. The anterior lobe, pars anterior, or adenohypophysis is derived from the anterior wall of Rathke’s pouch, an ectodermal structure that also forms the primitive oral cavity and the pharynx . The anterior gland contains a heterogeneous cellularity that synthesized and secreted hormones in the blood stream: the majority of the cells are somatotrope cells that produced the human growth hormone (hGH) or somatotropin hormone (STH), a peptide that promotes growth in childhood. The production of the somatotropic hormone is under the control of the hypothalamic growth-releasing hormone (GRH) produced by the arcuate nucleus. The next hormones produced in high quantity by the anterior gland of the hypophysis are the corticotrope ones (adrenocorticotropic hormone—ACTH, melanocyte-stimulating hormone—MSH, and beta-endorphins). This group of hormones is under the control of the hypothalamic corticotropin-relasing hormones (CRHs) derived from the paraventricular nuclei. In smaller percentages, the adenohypophysis has population of cells that produced thyrotropes, gonadotropes, and lactotropes. Thyrotropes respond to signals from the hypothalamic thyrotropin-releasing hormone (TRH) produced in the paraventricular nuclei and further synthesize the hormone responsible for thyroid hormones production—thyroid stimulating hormone (TSH). Luteinizing hormones (LHs) and follicle stimulating hormones (FSHs) are secreted by gonadotrope cells of the gland under the influence of pulsatile secretion of gonadotropin-releasing hormone (GRH) produced in hypothalamus preoptic area. The secretion of prolactine (PRL) from the lactotropes is stimulated by hypothalamic thyrotropinreleasing hormone (TRH) and inhibited by the dopamine. Hypothalamic hormones reach the adenohypophysis through a vascular system. Hypothalamus exerts its effects over the anterior part of the gland through the hypothalamo-hypophyseal portal system, a special vascular system formed by fenestrated capillaries. The proximal vascular structure of the portal system is the anterior hypophyseal artery, branch from the ophthalmic segment of the internal carotid artery. Through it, hypothalamic hormones are transported to the primary plexus, located near the infundibulum of the hypothalamus. From this region, hormones are drained into the second vascular venous plexus of the hypothalamo- hypophyseal portal system that surrounds the adenohypophysis. This vascular system allows hormones to diffuse through the wall, inside of the gland. The hypophyseal vein further drains the blood into the venous sinuses of the dura mater and from here in the venous system of the body.

The posterior wall of Rathke’s pouch forms the intermediate lobe of the gland [8]. It is absent or of small size in adults. In children, it is the part of the gland responsible for skin pigmentation through the secretion of the melanocyte stimulating hormone (MSH) or “intermedins”. Pars intermedia also produces corticotrophin-like intermediate lobe peptide (CLIP) and adrenocorticotrophic hormone (ACTH). The posterior lobe of the gland, pars distalis or neurohypophysis derives from the neuroectoderm. It is an inferior extension of the hypothalamus and is mainly from its neural fibers. The connection between the hypothalamus and the posterior lobe of the gland forms the infundibular stalk. Through this complex, hormones synthetized in the hypothalamus nuclei are transported and deposited in the posterior gland where they are stored in presynaptic vesicles and then released into the blood stream. The supraoptic nuclei of the hypothalamus are responsible for the secretion of antiduretic hormone (ADH) or vasopressin, the hormone involved in maintaining the water balance in organism and thus in preventing dehydration. The paraventricular nuclei produce oxytocin, a hormone released during labor, in the presence of uterine contractions. The hypothalamus intervenes along with the pituitary gland the majority of the endocrine and metabolic functions of the body through a double-sense transport of hormones between the two structures. The primary target of hypothalamic neuroendocrine cells is the pituitary gland, comprising the anterior pituitary (adenohypophysis) and the posterior pituitary (neurohypophysis). Some species also possess an intermediate pituitary lobe. Hypothalamus communicates with the anterior pituitary (Adenohypophysis) by hypothalamo-hypophysial portal system. Secretion of anterior pituitary is controlled by either hypothalamic releasing or hypothalamic inhibitory hormones or factors which were secreted within hypothalamus and communicate with anterior pituitary though hypothalamo-hypophysial portal system. On the other hand secretion from the posterior pituitary is controlled by the nerve signals that originates in hypothalamus and terminate to posterior pituitary via neurosecretory tract.

Hypophyseal portal system

The hypophyseal portal system is a system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary. Its main function is to quickly transport and exchange hormones between the hypothalamus arcuate nucleus and anterior pituitary gland. The capillaries in the portal system are fenestrated (have many small channels with high vascular permeability) which allows a rapid exchange between the hypothalamus and the pituitary. The main hormones transported by the system include gonadotropin-releasing hormone, corticotropin-releasing hormone, growth hormone–releasing hormone, and thyrotropin-releasing hormone. Structure: The blood supply and direction of flow in the hypophyseal portal system has been studied over many years on laboratory animals and human cadaver specimens with injection and vascular corrosion casting methods. Short portal vessels between the neural and anterior pituitary lobes provide an avenue for rapid hormonal exchange. Specifically within and between the pituitary lobes is anatomical evidence for confluent interlobe vessels, including venules providing blood from the anterior to the neural lobe, and capillary shunts exchanging blood between the intermediate and neural lobes. Such microvascular structures indicate moment-to-moment streams of information between lobes of the pituitary gland. Results of other studies showed that the neural hypophyseal stalk and ventromedial region of the hypothalamic arcuate nucleus receive arterial blood from ascending and descending infundibular branches and capillaries, coming from arteries of the superior hypophyseal arterial system. Small ascending vessels arising from the anastomoses that connect the upper with the lower hypophyseal arterial system also supply blood to hypophyseal vessels. Many of these branches are continuous between the proximal arcuate nucleus and anterior pituitary, enabling rapid hormone exchange. Other evidence indicates that capillary perivascular spaces of the median eminence and arcuate nucleus are contiguous, potentially facilitating hormonal messages between systemic blood and the ventral hypothalamus. Function: Peptides released near the median eminence from hypothalamic nuclei are transported to the anterior pituitary, where they apply their effects. Branches from the internal carotid artery provide the blood supply to the pituitary. The superior hypophyseal arteries form the primary capillary plexus that supplies blood to the median eminence. From this capillary system, the blood is drained in hypophyseal portal veins into the secondary plexus. The peptides released at the median eminence enter the primary plexus capillaries. From there, they are transported to the anterior pituitary via hypophyseal portal veins to the secondary plexus. The secondary plexus is a network of fenestrated sinusoid capillaries that provide blood to the anterior pituitary. The cells of the anterior pituitary express specific G protein-coupled receptors that bind to the neuropeptides, activating intracellular second messenger cascades that produce the release of anterior pituitary hormones. The following is a list of hormones that rely on the hypophyseal portal system to indirectly mediate their function by acting as a means of transportation from various nuclei of the hypothalamus to the anterior pituitary.

 Gonadotropin-releasing hormone (GnRH): regulates the release of follicle stimulating hormone and luteinizing hormone from the anterior pituitary; this pathway plays a critical role in reproductive activity and development

 Corticotropin-releasing hormone (CRH): regulates the release of adrenocorticotropic hormone from the anterior pituitary; this cascade is primarily responsible for stress responses

 Growth hormone-releasing hormone (GHRH): regulates the release of growth hormone from the anterior pituitary; as the name suggests, its main function is to help control cell growth, metabolism, and reproduction

 Thyrotropin-releasing hormone (TRH): regulates the release of thyroid-stimulating hormone from the anterior pituitary; functions to mediate various responses in the thyroid gland, including additional hormone synthesis

Clinical Significance: Over- or under-function as well as insufficiencies of the hypothalamus or the pituitary gland can cause a negative effect on the ability of the hypophyseal portal system to exchange hormones between both structures rapidly. This can have major effects on the respective target glands, making it impossible for them to carry out their functions properly. Occlusions and other issues in the blood vessels of the hypophysial portal system can also cause complications in the exchange of hormones between the hypothalamus and the pituitary gland.

The hypophyseal portal system also plays an important role in several diseases involving the pituitary and central nervous system. In several cases of hypophyseal and pituitary metastatic tumors, the portal system acts as the pathway for metastasis from the hypothalamus to the pituitary. That is, cancerous cells from the hypothalamus multiply and spread to the pituitary using the hypophyseal portal system as a means of transportation. However, because the portal system receives an indirect supply of arterial blood, tumor formation in the anterior pituitary is less likely than in the posterior pituitary. This is because the posterior pituitary is vascularized by direct arterial blood flow.[8][9] Pituitary apoplexy is described as hemorrhaging or reduction of blood supply to the pituitary gland. The physiological mechanisms of this condition have not been clearly defined in current research. It has been suggested, nonetheless, that damage to the leads to an obstruction of blood flow in the hypophyseal portal system and contributes to this defective state. In Erdheim-Chester Disease, cells of the immune system called histiocytes proliferate at an abnormal rate causing a plethora of symptoms and, in more severe cases, death. The disruption of the hypophyseal portal system has been implicated as the mechanism for several symptoms involving the central nervous symptom, most notably diabetes insipidus. Some disorders of the pituitary gland

Pituitary disorders generally occur when the pituitary gland is either too active or not active enough. Often there is a discrete piece of pituitary gland which leads to the problems, this is called a pituitary adenoma (if it is large it may be called pituitary macroadenoma). These are usually benign, non-cancerous tumours. Pituitary adenomas can cause problems through: 1. Releasing excess of one or more hormone. 2. Not releasing any hormones but pressing on the normal pituitary tissue and thus interfering with normal function; and/or 3. Causing pressure on nearby structures - for example, pressing on the nerve of the eye, leading to blurred vision or loss of part of the vision. Conditions where the pituitary gland produces too much of one or more of its hormones include:

 Acromegaly

 Cushing's syndrome

 Prolactinoma

Conditions where the pituitary gland fails to produce enough hormones include:

 Adult growth hormone deficiency.

 Diabetes insipidus.

 Hypopituitarism.

 Pituitary tumours.

 Tumours of, or injury to, the hypothalamus, having a knock-on effect on the pituitary gland.

How are pituitary disorders diagnosed? The diagnosis usually involves hormone blood tests and also brain scans. Hormone blood tests can be taken randomly for some hormones, but others may require specialised testing with substances that should provoke the release or prevent release in certain conditions. This may require attendance at a day unit and having several hormone blood tests throughout the day. Usually an MRI scan of the pituitary gland is undertaken to look for pituitary abnormalities - eg, pituitary adenoma or cysts.

What is the treatment for pituitary disorders? This will depend upon the cause. If there is hormone deficiency then this may need replacement with tablets. If a tumour is discovered as the cause of the problems then pituitary surgery may be required. This is usually via the nose. If there is a pituitary tumour which is found to be cancerous then radiotherapy may be needed after surgery. There may also be a need for lifelong hormone replacement following any treatment.