PHYSIOLOGY OF THE ADENOHYPOPHYSIS

Three efferent systems emerge from the brain and spinal cord. Two are neural-the somatic and visceral efferent systems. The third is humoral -the neuroendocrine system. The somatic efferent system employs striated muscle cells to move the organism or its component parts in response to environmental stimuli. The visceral efferent system employs smooth muscle cells and exocrine gland cells to regulate vascular function and to assimilate nutrients. The neuroendocrine system employs the pituitary gland to regulate the function of selected visceral organs (kidney, uterus, and breast), to regulate growth, and to trophically support and regulate the function of specific target organs of internal secretion ­the thyroid gland, adrenal gland, and gonads. Through the pituitary gland the brain affects the growth and development of the organism, maintains its internal milieu, regulates its metabolism, and assures its reproduction.

The Adenohypophysis

The pituitary gland is also called the hypophysis cerebri (from the Greek hypo-, below, and phuein, to grow). It is composed of glandular and neural tissue and hence is subdivided into an adenohypophysis and a neurohypophysis. The glandular cells that make up the adenohypophysis may be viewed as the effector cells of the neuroendocrine system. They perform this role by synthesizing protein hormones and secreting them into nearby capillaries. The adenohypophysis is not generally believed to be a neural diverticulum but is thought to arise instead from the primitive foregut-the stomodeum. A diverticulum of the stomodeum is believed to migrate cranially, pinch off from the foregut, and become applied to a neural diverticulum emerging from the diencephalon- the neurohypophysis. With the establishment of vascular connections between the neurohypophysis and the displaced foregut tissue, differentiation of the stomodeal remnant into the adenohypophysis occurs. However, this classic scheme has been challenged with the recognition that some adenohypophyseal cells contain S-100 protein and others are capable of amine precursor uptake and decarboxylation and thus can be considered as part of the APUD system. Cells in the APUD system are believed to be of neural origin (frequently originating from the neural crest). Takor and Pearse have suggested that the "ventral neural ridge" gives rise to the adenohypophysis and thus that the adenohypophysis is of neuroectodermal, not stomodeal, origin. The finding that some hypothalamic neurons are capable of synthesizing adrenocorticotropic hormone and melanocyte-stimulating hormone (hormones that are also synthesized in adenohypophyseal cells) strengthens the argument that at least some adenohypophyseal cells migrate from the brain to the adenohypophysis. The observation that adenohypophyseal cells look epithelial (glandular) does not vitiate the argument, as adrenal medullary cells (which are neural crest derivatives) are also glandular in appearance. However, little supportive evidence for a neural origin of the adenohypophysis has emerged subsequently. An ectodermal origin, similar to that of the salivary glands, seems likely for most elements in the adenohypophysis.

The adenohypophysis is made up of connective tissue, fenestrated capillaries, and epithelial cells. These cells secrete eight known hormones-growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), and endorphin (β-END). The epithelial cells that secrete these hormones are organized into a glandular pattern and can be characterized on the basis of their reaction with acid or basic dyes. In the human, most cells (52 percent) contain clear cytoplasm that does not stain with these dyes (chromophobes); 34 percent have cytoplasmic granules that stain with acid dyes (acidophils or eosinophils); and 14 percent contain cytoplasmic granules that stain with basic dyes (baso­phils). It has long been recognized that acidophils secrete GH or PRL and that basophils secrete TSH, FSH, LH, or ACTH. Elaborate classification schemes based on tinctorial properties of cells after complex staining procedures have been proposed to further relate epithelial cell structure to secretory function, but all these have failed.

Transmission electron microscopy (TEM) demonstrates that these epithelial cells contain large nuclei with dense chromatin and a single nucleolus. The cytoplasm has a well-developed Golgi apparatus, abundant rough endoplasmic reticulum, and large, dense core vesicles, which are sites of hormone storage. The sequence of amino acids making up the hormones is encoded in nuclear DNA. This information is in turn encoded in messenger RNA (mRNA) by the process of transcription, and the mRNA conveys it to ribosomes in the cytoplasm. A large body of evidence supports the concept that amino acids are united in an orderly sequence on ribosomes to form peptide prohormones-the process of translation. These large prohormones in turn are inserted into the cisternae of the endoplasmic reticulum. Membranes of the endoplasmic reticulum are pinched off to form lucent vesicles. These vesicles transport the prohormone to the cis face of the Golgi apparatus, and the prohormone is then passed through the Golgi complex in a cis-trans sequence for modification by phosphorylation, glycosylation, or sialylation as required for the assembly of a particular pituitary hormone. In addition, posttranslational cleavage of peptide bonds to form the final hormone product begins in the Golgi apparatus. Large, electron-dense secretory granules containing the processed hormone are assembled at the trans face of the Golgi apparatus. These secretory granules serve as storage sites for the hormones. On stimulation, the secretory granules migrate to the plasmalemma and unite with it, forming omega (Ω) figures. The contents of the secretory granules are released by exocytosis.

Attempts were made to devise a functional classification of adenohypophyseal cells on the basis of their electron microscopic appearance (shape and size of cells and distribution of vesicles) soon after these cells were first characterized ultrastructurally. Functional cell types were labeled by identifying the predominant cell type to appear after target organ ablation, then ascribing an appropriate tropic function to this cell type, and finally relating the cells to a particular cell population in the normal pars distalis. For example, corticotropes were identified by the appearance after adrenalectomy of "adenalectomy cells" that resembled a specific population of cells in the normal adenohypophysis. However, uncertainty remained when trying to distinguish between some cell types on the basis of TEM appearance alone.

With the advent of immunohistochemical procedures that stain hormones within cells. a method was developed to more certainly identify functional cell types in the adenohypophysis. At least six cell types have been identified (somatotropes, lactotropes, gonadotropes. thyrotropes. corticotropes, and melanotropes). The recent development of immunoelectron microscopy has added greatly to our knowledge of the morphology of functional cell types in the adenohypophysis. First. it has demonstrated that every pituitary hormone does not reside in its own cell type. Whereas TSH is uniquely found in thyrotropes, gonadotropes usually contain both FSH and LH. GH and PRL are usually found in separate cells, but examples of mammosomatotropes have been found in several species, including humans. Second, immunoelectron microscopy has shown that the ultrastructural morphology of a given cell type varies with the age of the animal, the hormonal milieu, and the functional state of the cell. An example of this morphologic variation is found in the rat lactotrope. Three types of lactotropes have been described by Kurosumi and colleagues. Type I cells are large and crescentic, with big secretory granules (~500 nm) arrayed around the periphery of the cell. Type II cells are smaller and are polygonal in shape. They are more granulated than type I cells, but the granules are small (~150 to 200 nm). Type III cells are small and polygonal and contain only a few very small (~ 100 nm) secretory granules. In adult males. 46 percent of the lactotropes are type I, whereas in adult females 91 percent are type I. Type III cells predominate in the perinatal period but are almost absent in adult­hood.

Functional cell types in the pars distalis may not be immutable. Conversion of somatotropes to mammotropes under the influence of estrogen has been shown experimentally. In rats, propylthiouracil treatment has been observed to cause transdifferentiation of somatotropes into thyrotropes. Pluripotent cells capable of differentiating into corticotropes or thyrotropes have been demonstrated by immunohistochemistry and hybrid histochemistry.

In most species, the adenohypophysis is divided into three regions- the pars tuberalis, pars intermedia, and pars distalis. The pars tuberalis is applied to the surface of the median eminence and the upper infundibular stem- rostral regions of the neurohypophysis. It is an extension of the glandular pituitary that lies above the sella turcica, applied to the base of the brain in the subarachnoid space. It is made up of epithelial cells, fenestrated capillaries, and stromal cells. The epithelial cells have been divided into pars tuberalis- specific cells, invasive cells, and follicular cells. Pars tuberalis cells have a unique ultrastructural appearance. They are spheroidal and contain glycogen granules and large numbers of lysosomes, as well as a few small secretory granules at the vascular pole. They immunostain weakly for TSH. The invasive cells appear to be gonadotropes, because they contain secretory granules and stain with antiserum to LH. Follicular cells are characterized by the presence of microvilli and cilia at their apical surface. The role of the pars tuberalis has not been firmly established, but studies suggest that it is involved with maintenance of short-loop feedback in the regulation of gonadotropes.

The pars intermedia, which is present in many species, is applied to the lower portion of the lower infundibular stem and the infundibular process-caudal regions of the neurohypophysis. It is made up of epithelial cells, with only a few capillaries and stromal cells. Dopaminergic nerves are found in it and terminate near glandular cells. Immunohistochemical and physiological studies have demonstrated that its epithelial cells contain α-MSH and β­endorphin. The pars intermedia is present in the human fetus and in pregnant adult women but is absent in adult men and nonpregnant women. However, in adult humans, basophilic epithelial cells are frequently found invading the neural lobe, and immunohistochemical procedures demonstrate many cells containing α-MSH closely apposed to the neurohypophysis. It appears likely that these cells form a functional unit analogous to the pars intermedia of other species.

The pars distalis forms the bulk of the adenohypophysis. It is composed of epithelial cells arranged in a glandular pattern, folliculostellate cells arranged in a syncytium, and fenestrate capillaries. It contains no axon terminals. Immunohistochemistry has revealed lactotropes, somatotropes, gonadotropes, thyrotropes, corticotropes, and melanotropes in the pars distalis. Several studies have demonstrated that lactotropes and somatotropes lie predominantly in the lateral wings of the pars distalis, whereas thyrotropes and gonadotropes occupy its medial third-the "mucoid wedge," so called because the secreted hormones (TSH, LH, FSH) are glycoproteins. As this median zone is continuous with the pars tuberalis and contains similar functional cell populations, it is also termed the zona tuberalis. Corticotropes lie anteriorly in the mucoid wedge and over the surface of the lateral wings. The secretory product is predominantly ACTH and β-END. Corticomelanotropes lie posteriorly near the neural lobe, with a small number scattered throughout the pars distalis. Their secretory products are predominantly α-MSH and β-END.

Growth hormone and prolactin are peptide hormones with similar structures. Growth hormone affects the metabolic processes in all body tissues by stimulating protein synthesis. Its actions are mediated by somatomedin-C (an insulin-like growth factor), which is believed to be synthesized in the liver. Prolactin stimulates protein synthesis (milk production) in the estrogen-primed breast.

TSH, LH, and FSH are glycoproteins and are each made up of two subunits: an α chain and a β chain. The α chain, which is not biologically active, is common to the three hormones. The β chain is unique to each hormone and is biologically active. TSH supports thyroid structure and secretion. FSH supports growth of the ovarian follicle and spermatogenesis. LH supports the corpus luteum and estrogen and progesterone secretion in females and the Leydig cells and testosterone production in males. ACTH is a peptide of 39 amino acids which is secreted by corticotropes. α-MSH is a 13-amino-acid peptide secreted by melanotropes. The structure of α-MSH is the same as that of the first 13 amino acids of ACTH. ACTH supports the structure and function of the adrenal cortex to regulate the secretion of glucocorticoids. α-MSH acts to disperse melanophores in amphibian skin, but its role in humans is not well established.

The secretion of pituitary hormones from the pars distalis is regulated by several humoral mechanisms. Hormone secretion from target organs of the pituitary gland is maintained at appropriate levels by a feedback mechanism. A decrease in the level of a circulating target hormone is sensed by tropic adenohypophyseal cells, and the secretion of the appropriate trophic hormone is increased. Other hormones and cytokines can also alter pituitary function. For example, epinephrine released from the adrenal medulla stimulates the release of ACTH, and interleukins, either local or carried from distant sites, can also cause ACTH secretion. In addition to these humoral mechanisms, neural mechanisms are also employed to regulate pituitary function. The brain assists in the regulation of pituitary function by releasing hormones from nerve terminals in the pituitary.

The Neurohypophysis

The neurohypophysis is a diverticulum of the brain that makes its appearance in the human early in fetal life (at between 10 and 14 mm crown-to-rump length). The mature neurohypophysis is made up of axon terminals, specialized glial cells, and blood vessels. Several features are common throughout the neurohypophysis and serve to distinguish it from the hypothalamus. The neurohypophysis contains no neuronal cell bodies-only axons and axon terminals. Axons terminate in the perivascular space of fenestrated capillaries, not on neurons or their processes. The neurohypophysis lacks a blood-brain barrier. It regulates the function of the adenohypophysis, which is applied to it.

The neurohypophysis is subdivided into three regions on the basis of regional morphologic specializations: (1) the median eminence, (2) the infundibular stem, and (3) the neural lobe. The median eminence and the paired lateral eminences together make up the tuber cinereum, which is visible on the inferior surface of the brain lying caudal to the optic chiasm and rostral to the paired mamillary bodies. Because the median eminence forms the funnel-shaped floor of the third ventricle, it is also called the infundibulum. It is the rostral region of the neurohypophysis. The infundibular stem is the neural portion of the pituitary stalk.

The neural lobe (also called the infundibular process) is the caudal region of the neurohypophysis. The classification of the neurohypophysis into these three portions stresses the observation that it is a diverticulum of brain and is distinct from the hypothalamus with which it is contiguous.

The infundibulum, the floor of the third ventricle, is separated into an ependymal layer, an internal zone, and an external (or palisade) zone. Its ependymal layer is made up of specialized epithelial cells. They are united by zonulae occludens (tight junctions), which inhibit the passive exchange of materials between the third ventricle and the interstitial fluid of the infundibulum. These cells lack cilia at their ventricular (apical) surface, which instead is characterized by the presence of large blebs as well as numerous smaller microvilli. Some of these ependymal cells are stretched ("tanycytes"), with their apical surface facing ventricular fluid and their basilar processes terminating in the perivascular space of fenestrated capillaries on the surface of the median eminence. Such cells do not resemble the ependymal cells lining the walls of the third ventricle, which are cuboidal, have cilia at their apical surface, lack apical blebs, and are united by gap junctions and desmosomes. The ependymal cells that line the infundibulum resemble the ependymal cells lining the rudimentary neural tube during embryonic development.

The internal zone of the median eminence is made up of axons of the supraopticohypophyseal tract, which originate in the hypothalamic supraoptic and paraventricular nuclei and pass through the median eminence to terminate in the neural lobe. The supraopticohypophyseal tract is selectively stained by acid fuchsin techniques in histologic studies and by antibodies to vasopressin and oxytocin (OT) for immunohistochemical studies. Its axons are typically large (magnocellular). These magnocellular axons show dense core vesicles (150 to 300 nm in diameter) on TEM. Small (parvicellular) fibers and terminals containing ACTH, α-MSH, and β-END also lie in the internal zone. In addition to peptidergic fibers, noradrenergic fibers and terminals have been demonstrated in the internal zone by formaldehyde fluorescence techniques. These fibers are believed to originate outside the hypothalamus in the brain stem and to represent the terminus of the ascending reticuloinfundibular tract.

The external zone of the median eminence is made up of glial cells, axons, and axon terminals. The axon terminals lie in the perivascular space of fenestrated capillaries. They are smaller than the terminals in the neural lobe and are part of the parvicellular neurosecretory system. Early investigators noted that these terminals could be separated into two classes based on the types of vesicles they contain: (1) terminals containing only small (50 nm), lucent vesicles and (2) terminals containing both small, lucent synaptic vesicles and large, granular vesicles (~100 nm). Subsequent studies have shown that the small, lucent vesicles contain synapsin and synaptophysin and thus resemble the synaptic vesicles found in terminals throughout the brain. Immunoelectron microscopic studies have localized peptide neurosecretory hormones in the large granular vesicles.

The disposition of terminals in the external zone has not been well characterized in humans but has been detailed in other mammals. The external zone has long been recognized as the site where the dopaminergic tuberoinfundibular tract terminates. It has also been recognized as a site where releasing hormones are secreted by hypothalamic neurons. At one time, a strict distinction was thought to exist between hypothalamic parvicellular neurons, which projected to the median eminence and released catecholamines (aminergic neurons), and hypothalamic parvicellular neurons, which projected to the median eminence and released hypothalamic hypophysiotropic hormones (peptidergic neurons). It was assumed that each terminal contained only one biologically active substance that was destined to be carried from the median eminence to the pars distalis to regulate its function. This assumption has proven to be false; the discovery of colocalization of peptides and transmitters in terminals of the median eminence has blurred the distinction between aminergic and peptidergic neurons.

Terminals containing thyrotropin releasing hormone (TRH) reside in the external zone of the median eminence. TRH stimulates the release of TSH from thyrotropes. Terminals that contain corticotropin releasing hormone (CRH) also reside there, but many of these terminals co-store arginine vasopressin (AVP). Some co­store angiotensin (ANGII), and some neurons contain all three hormones. Each hormone acts to stimulate the release of ACTH from corticotropes. The actions of CRH and AVP are not only additive but synergistic. The terminals that contain TRH, CRH, somatostatin (SRIF), or growth hormone releasing hormone (GRH) all lie in the medial third of the external plexus in the rat. Terminals that contain gonadotropin releasing hormone (GnRH) are present in the external zone; but, in the rat, they are located in the lateral thirds of the median eminence as seen in coronal section. The distribution of parvicellular terminals in the human median eminence has not been characterized.

Dopaminergic terminals are also present in the external zone of the median eminence. They have been identified by their characteristic fluorescence after exposure to formaldehyde vapours or to gyloxylic acid or by the immunohistochemical identification of tyrosine hydroxylase in them. Tyrosine hydroxylase-like (TH-li) terminals are presumed to be dopaminergic. Dopamine inhibits the release of PRL from lactotropes. Neurotensin (NT), galanin (GAL), and gamma amino butyric acid (GABA), have all been colocalized in TH-li terminals in the rat median eminence.

The infundibular stem lies between the infundibulum and the infundibular process. It is characterized by the presence of axons of the supraopticohypophyseal tract. The infundibular process (neural lobe) is the terminus of the supraopticohypophyseal tract, the axons of which terminate in the perivascular space of neural lobe capillaries. Some parvicellular systems also terminate in the neural lobe in the human.

The Portal System: Transfer of Information from Neurohypophysis to Adenohypophysis

In the somatic efferent system, information is carried as a pattern of neural impulses by ventral horn cells that are the final common pathway to striated muscle cells. The pattern of impulses carried along the ventral horn cells is determined by segmental and suprasegmental (descending) input across chemical synapses, and the information reaches the target (muscle) cell through a chemical synapse at the myoneural junction. The central nervous system employs the mechanism of neurotransmission to cause the effector organ (striated muscle) to exert a force over a distance with considerable precision.

In the visceral efferent system, a similar arrangement is found. Suprasegmental and reflex (segmental) inputs converge on cell bodies in the intermediolateral cell column (or in visceral efferent cranial nerve nuclei), the axons of which serve as the final common pathway to the effector organ. In the case of cardiovascular regulation, the effector organ is again a muscle cell (smooth or cardiac). The visceral efferent system also regulates glandular secretion-for example, gastrointestinal, salivary, lacrimal, pineal and choroid plexus secretions. In this system, postganglionic neurons make synaptic contact with secretory epithelial cells. In the case of the adrenal medulla, preganglionic neurons make synaptoid contact with cells that originated in the neural crest and have been modified into secretory epithelium. The secretory activity of glandular cells is regulated by the central nervous system in a manner analogous to the regulation of muscle cells. Descending (suprasegmental) and reflex (segmental) inputs are integrated into the final common pathway to regulate the performance of chemical work by secretory epithelial cells (as opposed to mechanical work by muscle cells).

The third efferent system-the neuroendocrine system-may be viewed in an analogous manner. In this system, the effector organ is a secretory epithelial organ that performs the chemical work of synthesizing and secreting hormones. These secretory epithelial cells, like muscle cells or exocrine glandular cells, lie at some distance from the central neural elements that control their function. However, the final common pathway to these endocrine cells is not axonal but vascular, and the information is carried to the pituitary (effector) cells by neurohormones, which are released in a pulsatile pattern from neurohypophyseal axon terminals by the process of neurosecretion into restricted vascular channels that pass to the adenohypophysis.

Since the blood vessels in the pituitary gland are the final common pathway from the terminals in the neurohypophysis to the effector cells in the adenohypophysis, their anatomy merits attention. The three neurohypophyseal regions share a common capillary bed. It is supplied rostrally at the median eminence by the superior hypophyseal arteries, which arise from the intracranial internal carotid arteries, the proximal (A1) segments of the anterior cerebral arteries, and the posterior communicating arteries; and it is supplied caudally at the neural lobe by the inferior hypophyseal arteries. In several species there is a third source of arterial supply, variously called the trabecular artery, the loral artery, the anterior hypophyseal artery, and the artery to the infundibular stem, depending on the species studied. As this vessel supplies the infundibular stem and arises along the course of the internal carotid artery between the superior and inferior hypophyseal arteries, the name middle hypophyseal artery seems appropriate.

The neurohypophyseal capillary bed is specialized at its rostral pole into a complex median eminence (primary) capillary plexus. This plexus is subdivided into an external (mantle) plexus and an internal plexus of complex capillary loops and coils. The external plexus lies on the median eminence surface, interposed between the median eminence and the pars tuberalis. Its fenestrated capillaries lie in close proximity to axon terminals in the external zone of the median eminence. The internal plexus arises from the external plexus, and its complex vascular formations penetrate the median eminence neuropil. Some (short) capillary loops penetrate only through the external zone, whereas other (long) capillary loops penetrate through the external and internal zones to the subependymal region before returning to the surface of the median eminence.

The neurohypophysis is drained rostrally by a series of fenestrated portal vessels that are interposed between the median eminence primary plexus and the pars distalis secondary plexus. These portal vessels drain both the external and the internal plexus. Capillary connections between the median eminence and the pars distalis are also ample. In addition, drainage routes from the median eminence to the hypothalamus and to the veins at the cerebral base have been demonstrated in several species. The rostral region of the neurohypophysis has limited drainage to the general circulation, but ample local drainage to the pars distalis.

The neurohypophysis is drained caudally (at the level of the neural lobe) by paired posterior hypophyseal veins, which course parallel to the inferior hypophyseal arteries and drain to the posterior cavernous sinus lateral to the midline. In addition, capillary connections unite the neural lobe with the adjacent pars distalis, and, in some species (for example, the rat). a series of short portal vessels also unite the neural lobe with the pars distalis. The caudal region of the neurohypophysis has ample drainage to the general circulation but somewhat limited local drainage to the adjacent pars distalis.

The adenohypophysis does not receive a direct arterial supply; the blood entering it passes first through the neurohypophysis. The venous drainage of the adenohypophysis is from the pars distalis to the adjacent cavernous sinus. The primary drainage routes are through the same posterior hypophyseal veins that drain the neurohypophysis. These veins are Y -shaped, with one arm draining the caudal neurohypophysis and the other draining the caudal pars distalis; the arms unite into a common stem that drains into the posterior cavernous sinus. In addition, small lateral hypophyseal veins course from the lateral wings of the pars distalis into the lateral cavernous sinus.

The direction of blood flow in the pituitary gland has been deduced from histologic examination of the gland after sectioning of the stalk and from direct observations of the flow of blood from the median eminence down the anterior surface of the pituitary stalk to the pars distalis in living animals. The pattern of blood flow on the surface of the entire gland has been recorded. Blood enters the neurohypophysis at each end (the median eminence and the neural lobe) almost simultaneously. However, because the inferior hypophyseal arteries lie closer to the heart than the superior hypophyseal arteries, blood enters the neural lobe just prior to entering the median eminence. Within the neurohypophysis, blood flow between different regions occurs. It flows retrograde from the neural lobe into the lower infundibular stem and anterograde from the median eminence into the upper infundibular stem. The infundibular stem is thus a watershed zone, receiving blood from both the median eminence and the neural lobe. The site in the infundibular stem where the ascending and descending wave fronts meet varies. Rostrally the median eminence drains rapidly to the pars distalis. Caudally the neural lobe and infundibular stem drain to the cavernous sinus through posterior hypophyseal veins. Some blood does cross from the neural lobe into a small zone of the adjacent pars distalis. The bulk of the pars distalis, however, receives its blood from the median eminence. Blood passes down the pituitary stalk into the medial third of the pars distalis and courses into the lateral wings. A small region in the lateral wings of the pars distalis drains to the lateral cavernous sinus through lateral hypophyseal veins. Most of the blood sweeps dorsomedially to the junction of the pars distalis and neural lobe, where it drains into the Y-shaped pituitary veins, which in turn drain to the posterior cavernous sinus. Sectioning of the stalk markedly alters the pattern of blood flow. No blood enters the pars distalis through portal routes from the median eminence. The small territory of the pars distalis supplied from the neural lobe diminishes if the blood pressure falls.

Although the physiology of pituitary blood flow has come under close scrutiny, a composite picture cannot as yet be presented. Pars distalis blood flow in the rat and dog is about 70 cm³/100 g per minute, and neurohypophyseal blood flow in the sheep is much higher-about 450 cm³/100 g per minute. This flow is about 8 times the cortical blood flow and 10 times the hypothalamic blood flow in the same animals. Flow in the median eminence does not differ from that in the neural lobe. Neurohypophyseal blood flow is autoregulated and decreases with hypocarbia. In these respects it is similar to cerebral blood flow, a finding that should not be unexpected in a brain diverticulum. As neurosecretory cells terminate on median eminence capillaries that drain to the pars distalis via portal routes and on capillaries in the infundibular stem and neural lobe that drain to the adjacent pars distalis, the entire neurohypophyseal capillary bed may be viewed as the final common pathway to the pars distalis. The vascular arrangements in the pituitary gland assure the delivery of neurosecretions from the neurohypophysis to the adenohypophysis over local routes at high rates of flow.

Neurosecretion into neurohypophyseal vessels provides the mechanism by which the brain controls adenohypophyseal function. The Scharrers proposed the concept of neurosecretion. They suggested that some neurons could function as glandular cells, synthesizing and releasing hormones. Subsequently, the hormones AVP and oxytocin (OT) were isolated from the neural lobe and the hypothalamic supraoptic and paraventricular nuclei. With the demonstration that OT and AVP are synthesized in these hypothalamic regions, transported by axoplasmic flow through fibers in the supraopticohypophyseal tract to axon terminals in the neural lobe, and released under appropriate physiological conditions, the concept of neurosecretion was established and the means by which the brain controls neural lobe function was clarified. In 1947, Green and Harris demonstrated that the pars distalis lacks axon terminals, and they suggested that a neurovascular link between the median eminence and pars distalis controlled anterior pituitary function. They postulated that chemical messengers are released from axon terminals that lie in the perivascular space of capillaries in the median eminence, enter these capillaries, and are transported by restricted portal routes to target cells in the pars distalis.

Hormones were found in the median eminence and medial basilar hypothalamus by bioassay; and, they regulated adenohypophyseal function. Several of these peptide hypothalamic hypophysiotropic hormones have been isolated, sequenced, and synthesized. GnRH stimulates the secretion of both FSH and LH by gonadotropes. TRH stimulates the release of TSH by thyrotropes. CRH stimulates the release of ACTH by corticotropes. GRH stimulates the release of growth hormone from somatotropes, whereas somatostatin SRIF inhibits it. In addition, evidence is accumulating that dopamine is a physiological prolactin-inhibiting factor.

In the somatic efferent system, specificity of response is assured by the close proximity of the axon terminal to the muscle cell, the isolation of the synapse at the myoneural junction, and the specificity of receptor sites on the muscle cell membrane. In the pars distalis, epithelial cells are virtually bathed in blood containing a host of hypothalamic releasing and inhibiting hormones. These hormones interact with specific receptors on the cell surface of target pituitary epithelial cells to activate a cascade of intracellular second messengers that stimulate or inhibit the synthesis and release of adenohypophyseal hormones. There is accumulating evidence that the releasing hormones GnRH and TRH stimulate intracellular cAMP production in gonadotropes and thyrotropes, and that the inhibiting hormones somatostatin and dopamine inhibit cAMP production in somatotropes and lactotropes. Increased production of ACTH by corticotropes depends on the activation of both cAMP and the calcium-calmodulin system. Stimulated release of PRL from lactotropes depends on the activation of phospholipid hydrolysis. The brain evokes a specific pituitary hormone response by releasing specific hypothalamic stimulating and inhibiting hormones, which interact with specific receptors on pituitary target cells.

In its simplest form, this schema involves three assumptions: (1) that the specificity of receptors at the adenohypophyseal cell surface is absolute, (2) that only one stimulating and/or releasing hormone governs the secretory activity of each functional pituitary cell type (i.e., that each adenohypophyseal cell carries only one population of surface receptors), and (3) that a single releasing hormone releases only one pituitary hormone. Regarding the first assumption, however, the specificity of hypothalamic hypophysiotropic hormones is not absolute. TRH administration stimulates the release of PRL as well as TSH, although the role of TRH in the physiologic control of PRL secretion has not as yet been established. Somatostatin inhibits the synthesis and release of hormones other than growth hormone. In certain pathologic conditions, for example adenoma formation, cellular receptors apparently lose their specificity. In some acromegalics, growth hormone secretion is stimulated by TRH infusion and is inhibited by the administration of dopamine agonists.

As for the second assumption, some adenohypophyseal cells respond to two or more hypothalamic peptidergic hormones.

Pituitary ACTH secretion is stimulated by AVP as well as CRH. Although the molar response of corticotropes to CRH is much stronger than to AVP, the effect of the two hormones combined is not simply additive but is synergistic. In addition, ACTH release can be increased by the levels of epinephrine that are reached under conditions of stress, via the stimulation of β-adrenergic receptors on corticotropes. Corticotropes have three receptor types (at least) on their cell surface. Each is activated by a specific agonist and in turn activates a cascade of second messengers.

Regarding the third assumption, although receptor specificity on the adenohypophyseal cell surface is a mechanism that would appear to guarantee that a specific pituitary hormone is released in response to a specific brain hormone, CRH apparently stimulates both the secretion of ACTH from corticotropes and the secretion of MSH from melanotropes in the rat pituitary. The explanation for this finding lies in the fact that the two cell lines carry out different posttranslational processing on the same prohormone. Both corticotropes and melanotropes translate the same prohormone (pro­opiomelanocortin) from mRNA. Both cleave this 31,000-dalton prohormone into a precursor hormone containing 130 amino acids. Corticotropes then cleave this precursor to form ACTH (amino acids 1 to 39) and β-END, whereas in melanotropes, ACTH is further cleaved into α-MSH (amino acids 1 to 13) and corticotropin-like intermediate peptide (CLlP).

The specificity of response may be aided by an endocrinotopic segregation of nerve terminals. Dopaminergic systems (from the arcuate nucleus) terminate in the external zone, principally in the lateral third. Norepinephrine-containing terminals of neurons arising in the brain stem terminate in the medial third of the median eminence, principally in the internal zone. CRH projections terminate in the medial third (internal and external zone), and AVP systems pass through the median eminence internal zone to the neural lobe but also terminate in the external zone in the medial third. Somatostatin-containing fibers terminate diffusely in the medial third, and TRH-containing fibers terminate in the external zone of the middle third. Therefore, the lateral thirds of the median eminence contain neurosecretory and catecholamine terminals (producing GnRH and dopamine) that are involved in regulating reproduction through the regulation of FSH, LH, and PRL secretion. The medial third produces the releasing hormones that are involved in regulating metabolism through GH and TSH secretion (somatostatin, GRH, and TRH) and in mediating the organism's response to stress through ACTH secretion (CRH and AVP). Portal vessels are so disposed as to carry hypothalamic hormones from the lateral regions of the median eminence to the lateral wings of the pars distalis and from the medial third of the median eminence to the mucoid wedge of the pars distalis.

Vascular elements need not be interposed between the neural terminal and adenohypophyseal secretory cells. The dopaminergic tuberohypophyseal tract terminates along the ventral surface of the infundibular stem and process, near melanotropes in the adjacent pars distalis whose adenyl cyclase and secretory activity are negatively coupled to dopamine concentration. In some regions, these adenohypophyseal cells invade the neural lobe. The proximity of nerve terminals to melanotropes provides another mechanism for specific control of adenohypophyseal function by the brain.

The specificity of the receptors at the adenohypophyseal cell surface for corresponding peptidergic hypothalamic hormones, the genetically determined translational pathways of (pro-) hormone synthesis, and the variations in post-translational processing of prohormones are the key mechanisms in assuring a specific adenohypophyseal response to neurohumoral instructions from the brain. The close relation of melanotropes to parvicellular terminals, which obviates the need for vascular transport of humoral signals, is a fourth such mechanism. The possibility that specific regions in the median eminence "project" by portal vessels to corresponding pituitary regions adds another potential mechanism of neural control of anterior pituitary function, and is presently being investigated (Table-1).

* RH = releasing hormone, IH = inhibiting hormone. POA = preoptic area, TN = tuberal nuclei, PVN = paraventricular nuclei, SON = supraoptic nuclei, ME = median eminence, NL = neural lobe.* PT = pars tuberalis, PO = pars distalis.

Surgical Correlates of Pituitary Anatomy

This anatomic survey has constructed a pituitary gland composed of a neurohypophysis (median eminence, infundibular stem, and neural lobe) and an adenohypophysis (pars tuberalis, pars intermedia, and pars distalis). The proposed model is quite different in some respects from the traditional teaching that the pituitary gland lies in the sella turcica and is bounded superiorly by the diaphragma sellae; that the median eminence is part of the hypothalamus; and that the pars tuberalis can be dismissed. That version arose from the habit of anatomists and pathologists of dividing the pituitary stalk when removing the brain from the skull thus keeping the median eminence and pars tuberalis with the brain and leaving a "pituitary gland" consisting of the pars distalis and neural lobe in the sella turcica. The traditional pituitary gland thus represents only half of the pituitary as defined here.

The model presented here raises two points of surgical interest. First, total hypophysectomy by the transphenoidal route becomes a difficult and dangerous task that involves removing the median eminence and pars tuberalis. Because infarction of the median eminence and pars tuberalis does not occur (in monkeys and rats) following either sectioning of the stalk or removal of the pars distalis and neural lobe, functioning tissue capable of secreting FSH and LH is left behind when only the pars distalis is removed. Indeed, in the rat, growth of this tissue occurs after hypophysectomy, with an increase in the number and size of functioning gonadotropes. to Second, knowledge of the distribution of cell types in the adenohypophysis makes it possible to predict the sites of small functioning pituitary tumors. Tumors that secrete GH or PRL will be found in the lateral wings of the pars distalis, whereas tumors secreting TSH or gonadotropins will be found more medially in the mucoid wedge or above the diaphragma sellae in the pars tuberalis. Tumors that secrete α-MSH or ,l3-endorphin may be expected to be closely apposed to the neural lobe, whereas ACTH­secreting tumors may be expected to begin anteriorly and inferiorly near the median plane.

Several points of surgical relevance also become apparent when one considers the portal system. (1) When vasopressors are infused during hemorrhagic shock to raise mean arterial blood pressure and restore cerebral blood flow, they will have no effect on cerebral vascular resistance because of the blood-brain barrier. However, in the pituitary gland, where there is no blood-brain barrier, pressor agents can reach the smooth muscle cells of resistance arterioles, causing them to constrict and decrease pituitary blood flow, with the result that pituitary infarction can occur even while cerebral blood flow is being restored. This mechanism may be the cause of Sheehan' s syndrome of postpartum pituitary necrosis. (2) Because the superior hypophyseal arteries that vascularize the median eminence and medial basilar hypothalamus lie in the subarachnoid space, subarachnoid hemorrhage with spasm of the vessels of the circle of Willis may be expected to reduce pituitary blood flow and alter pituitary function. This scenario will be masked by the administration of glucocorticoids. (3) Because the venous drainage routes from the pars distalis to the cavernous sinus lie lateral to the midline, it should be possible to lateralize small secretory pituitary tumors that are poorly visualized by radiologic studies by performing selective bilateral inferior petrosal sinus catheterization and taking blood samples for determination of hormone levels. (4) The venous drainage routes to the cerebral base from the median eminence are apparently adequate to prevent venous infarction of the median eminence after sectioning of the stalk or removal of the neural lobe and pars distalis. Therefore, if the pituitary gland in the sella has undergone destruction by a neoplasm or aneurysm or by traumatic stalk sectioning, it should be feasible to transplant the pituitary to sites beneath the median eminence, as only the portal vascular connections between the graft and the preserved median eminence need be re-established­ not neural connections.

Hypothalamic Anatomy

Endocrine "Motor" Neurons in the Hypothalamus

The chemical synthesis of peptide hypothalamic hormones has made it possible to identify them by immunohistochemistry in neurosecretory cells whose cell bodies lie in the hypothalamus and whose terminals lie in the median eminence. Neural hormones are synthesized in the neuronal soma (on rough endoplasmic reticulum) by the same steps that produce pituitary peptides in adenohypophyseal cells. The hormones are packaged in large, granular vesicles and transported by axoplasmic flow to the axon terminal lying in the perivascular space of a fenestrated capillary in the neurohypophysis where they are released by exocytosis under appropriate physiological conditions. Recent evidence suggests that the hormone translated from mRNA is frequently a prohormone, and that the cleavage of this prohormone occurs during axoplasmic transport.

In the rat, parvicellular neurosecretory neurons terminate in the rostral region of the neurohypophysis (the median eminence), and their neurosecretions regulate pars distalis function. In the human, the terminal sites of the parvicellular system are more widespread, with some lying in the neural lobe as well as the ones in the median eminence. A typical CRH-li parvicellular neuron in the rat hypothalamus is bipolar in shape, with a fusiform cell body 20 to 28 µm long by 10 to 12 µm wide. The nucleus is in folded and contains a prominent nucleolus. The Golgi apparatus and rough endoplasmic reticulum are prominent. Immunoreactive CRH is present on ribosomes in the cell body and in dendrites as well as in granular vesicles in the cell body and axons.

Hypophysiotropic neurons have been identified by combining retrograde tracing techniques with immunohistochemistry. Most of the work has been carried out in experimental animals such as the rat. so extrapolation to humans may be incorrect. For the most part, parvicellular neurosecretory cells are localized in nuclear clusters. GRH-li neurons are present in the arcuate nucleus, as are neurons that contain the prolactin inhibiting hormone dopamine. In humans, GnRH-li neurons are found aggregated anterior to the median eminence just beneath the arcuate nucleus as well as in the preoptic area. Hypophysiotropic SRIF-li neurons and TRH-li neurons are present in the anterior periventricular nucleus. CRH-li neurons are present in the paraventricular nucleus.

The anatomy of this nucleus is complex. It is composed both of magnocellular neurons that contain oxytocin or vasopressin and project to the neural lobe and of parvicellular neurons that contain CRH and project to the median eminence. These neuronal populations are segregated in the nucleus such that each region has a unique population of immunohistochemically identifiable cells and a unique pattern of input and efferent projection.

Parvicellular neurosecretory neurons synthesize and co-store hormones other than the classic releasing and inhibiting hormones, A population of CRH-li neurons co-store AVP and/or ANGII; another population of CRH-li neurons co-store vasoactive intestinal peptide (VIP) and metenkephalin; another costores neurotensin, and yet another costores galanin. Presumptive dopaminergic (TH­li) neurons can also be subdivided into different populations characterized by unique patterns of costored hormones. Immunoreactive glutamic acid decarboxylase (GAD) has been demonstrated in some TH-li neurons, suggesting that GABA and dopamine are cos­tored in the same neurons. GRF. neurotensin, choline acetyltransferase, and galanin have been colocalized in TH-li neurons by immunohistochemistry in different patterns. The significance of the hormonal profiles that define specific functional populations of hypothalamic neurosecretory cells is not well understood. Perhaps hormones and transmitters that are colocalized with releasing and inhibiting hormones act by autocrine or paracrine mechanisms to optimize the effect of neurohormone release.

Descending Fiber Systems to the Neurohypophysis

Neuronal cell bodies containing immunoreactive CRH in the parvicellular portion of the paraventricular nucleus project laterally from the nucleus along with the projections of the magnocellular AVP and OT neurons to enter the lateral retrochiasmatic area. This CRH projection then, passes posteromedially to enter the median eminence from the anterolateral preoptic region. Hypophysiotropic TRH-li neurons occupy both the anterior periventricular nucleus and the periventricular zone of the paraventricular nucleus in the rat. The largest population of immunoreactive neurons is found in the parvicellular division of the paraventricular nucleus. These neurons take a descending periventricular course to the median eminence. SRIF-li neurons that project to the median eminence also lie in the anterior periventricular nucleus and project to the median eminence by periventricular routes. TH-li neurons lie in the dorsomedial region of the arcuate nucleus, and GRH-li neurons lie in its ventrolateral aspect. These neurons too project to the median eminence. Taken together. the projections of CRH neurons from the paraventricular nucleus, the projections of SRIF-li neurons and TRH-li neurons from the anterior periventricular nucleus. and the projections of the TH-li neurons and GRH-li neurons from the arcuate nucleus constitute the tuberoinfundibular tract GnRH-containing perikarya are concentrated in the medial preoptic area rostral and dorsal to the chiasm in many of the commonly studied experimental animals with an estrus cycle. Menstruating primates, as noted, have a different distribution of GnRH-li neurons, with an aggregation of cells anterior and inferior to the arcuate nucleus. GnRH-containing cells in the preoptic area project through the preopticoinfundibular tract to terminate in the median eminence.

In addition to the parvicellular peptidergic system, which secretes hypothalamic releasing and inhibiting hormones, there is a second peptidergic system in the hypothalamus. The cell bodies of this system, which are located predominantly in the arcuate nucleus, contain the processed products of pro-opiomelanocortin­ACTH, β-lipotropin (β-LPH), α-MSH, and β-endorphin. The system projects to the median eminence. In addition, ACTH­containing projections from the arcuate nucleus to the parvicellular regions of the paraventricular nucleus have been demonstrated, as have projections containing α-MSH, β-endorphin, ACTH, and β-LPH to hypothalamic and extrahypothalamic brain areas.

Surgical Correlates of Hypothalamic Anatomy

If the anatomic findings described here can be extrapolated to humans, they have several implications that are relevant to surgery. (1) Tumors of the medial sphenoid ridge may alter anterior pituitary function without direct pituitary involvement by compressing hypothalamic-hypophysiotropic pathways. (2) Because pathways projecting from the paraventricular nucleus to the median eminence lie close to the third ventricle, they will be susceptible to injury by surgical procedures carried out in the third ventricle, as will the periventricular cell bodies. If the median eminence or pars distalis has been compromised by a tumor or by an operation to remove the tumor, damage to the periventricular hypothalamus will be masked, as is damage to the corticospinal tract or ventral horn cells when the target muscle is diseased or injured. (3) The anterior surgical approach to the third ventricle through the lamina terminalis must be kept strictly in the midline to avoid damaging fibers passing to the median eminence and neural lobe. (4) Damage to small vessels entering the anterior perforated space during aneurysm dissection will damage pituitary function as well as autonomic function and consciousness. The menstrual cycle and reproductive function in women of child-bearing age would appear to be particularly at risk. (5) Hydrocephalus with stretching of periventricular fibers may alter pituitary function. (6) The periventricular location of these hypophysiotropic fiber systems and the recovery of hypothalamic hormones from cerebrospinal fluid suggest that transplantation of pituitary tissue into the third ventricle, as well as beneath the median eminence, is feasible.

Extrasegmental Input to the Hypothalamus

The adenohypophyseal cells are viewed as being analogous to a motor organ such as skeletal muscle; the neurohypophyseal capillaries and the portal system are viewed as the final common pathway to these cells; and the neurosecretory cells and their fiber tracts containing hypophysiotropic peptides, which originate in the periventricular region of the hypothalamus and preoptic area and terminate near neurohypophyseal capillaries, are presented as analogous to segmental ventral horn cells. The tasks remaining are (1) to determine the extrasegmental neural inputs to hypothalamic neurosecretory cell groups, to clarify the mechanisms by which information converging on endocrine motor units is integrated; and (2) to determine the pathways of neural output from these hypothalamic cell groups, to clarify the mechanisms by which autonomic, motor, and mental activities are correlated with neuroendocrine function.

The role of descending suprasegmental input from the temporal lobes in the control of reproductive function has been demonstrated, but the anatomy of suprasegmental control of GnRH remains to be clarified. At the segmental level, we know that in the rabbit, preoptic stimulation in the region containing GnRH cell bodies elicits GnRH release into portal vessels, resulting in elevation of plasma LH levels and ovulation. We also know that lesions of suprasegmental neurons in the amygdala or of their efferent projections in the stria terminalis (which terminates in the sexually dimorphic nucleus of the stria terminalis in the preoptic area) alter the estrus cycle in the rat. In primates, the relationship between the medial temporal lobes and reproductive function is not clear. No change in neuroendocrine function was reported in adult female monkeys that had undergone bilateral anterior temporal lobectomy. However, alterations in the control of LH secretion have been reported in humans with temporal lobe epilepsy. The mechanism by which temporal lobe output modifies the release of FSH and/or LH from the pituitary gland awaits clarification of the descending input from the temporal lobe to the GnRH cells scattered in the preoptic area and (in humans) clustered beneath the arcuate nucleus.

There is a significant input from the amygdala and hippocampal formation to both the magnocellular and the parvicellular regions of the paraventricular nucleus, but it is not direct. The input to the parvicellular regions is via a relay in the bed nucleus of the stria terminalis. Input from the amygdala reaches the magnocellular regions of the paraventricular nucleus and the supraoptic nucleus through its projection to the ventromedial nucleus, thence to the dorsomedial nucleus and on to the regions where magnocellular neurosecretory neurons reside. In addition, projections from the septum (which in turn receives hippocampal input) to the paraventricular nucleus have been found. Stimulation of the dorsal hippocampus or of the septum inhibits firing in neurons that lie in the paraventricular nucleus and project to the median eminence. Excision of the hippocampi or sectioning of the fornices results in an increase in plasma cortisol levels. It seems reasonable to conclude that descending input from the temporal lobes inhibits ACTH release from corticotropes in the pars distalis via inhibition of the release of CRH from CRH-li neurons in the paraventricular nucleus.

The response to hypotension provides a model that permits insight into the mechanisms by which neuroendocrine and visceral responses are integrated by ascending infrasegmental input. Except in the case of feedback mechanisms, it is unusual for the organism to respond to a stimulus from the internal or external milieu by secreting only one pituitary hormone. For instance, in hypotensive shock, ACTH, β-END, and AVP are all released from the pituitary gland, and compensatory adjustments are also made by the visceral efferent (autonomic) system.

Hypotension causes an increase in neural traffic over the glossopharyngeal nerves, with increased input to the tractus and nucleus solitarius. Connections between the nucleus solitarius and the dorsal vagal motor nucleus have been found, as have connections between the dorsal motor nucleus and the lateral reticular nucleus. Ascending noradrenergic systems originating in the dorsal motor nucleus and in the lateral reticular nucleus have been demonstrated in the rat by the use of formaldehyde fluorescence techniques. Neurons from the noradrenergic (A2) region of the dorsal motor nuclei terminate in the parvicellular region of the paraventricular nucleus, where CRH-li cells reside. Projections from the noradrenergic region (A1) of the lateral reticular nucleus terminate in the magnocellular regions of the paraventricular nucleus and in the supraoptic nucleus in the regions where AVP-li cells reside. Adrenergic cells in the Cl and Cz regions of the lateral reticular nucleus and dorsal motor nucleus, respectively, project to the parvicellular regions of the paraventricular nucleus. There are neural connections between the parvicellular and magnocellular divisions of the paraventricular nucleus and between the paraventricular nucleus and the supraoptic nucleus. AVP is present in large neurons in the supraoptic and paraventricular nuclei that project to the neural lobe and in small paraventricular neurons (where it is co-stored with CRH) that project to the median eminence. The ascending noradrenergic tracts may thus regulate AVP secretion into median eminence and neural lobe capillaries, for transport locally to the adenohypophysis and for transport distantly to target organs (kidneys, systemic arterioles). CRH is present in axon terminals whose cell bodies lie in the parvicellular divisions of the paraventricular neurons. It is released by axon terminals lying in the median eminence and is carried to the pars distalis to stimulate ACTH release.

In the pars distalis, the increase in AVP and CRH secretion under hypotensive conditions has a synergistic effect on ACTH release, thus maximizing ACTH secretion and the stimulation of the adrenal cortex to secrete cortisol. The AVP released from the neural lobe is carried by systemic vascular routes to receptors on precapillary arterioles and to renal parenchymal cells to elevate mean arterial blood pressure and to increase renal water conservation, respectively. In addition, AVP secreted by the neural lobe may be carried by capillary routes to the adjacent pars distalis to stimulate ACTH release. In this manner a coordinated neuroendocrine response to a single stimulus, hypotension, may be elicited by the pituitary gland.

Neural Output from the Periventricular Hypothalamus

AVP-containing neurons in the paraventricular nucleus project caudally to terminate in the dorsal motor nucleus of the vagus on noradrenergic cells. A loop is thus formed, with noradrenergic cells in the dorsal motor nucleus of the vagus projecting to AVP­containing neurons in the paraventricular nucleus, and AVP­containing neurons projecting back to the dorsal motor nucleus of the vagus. In addition, paraventricular neurons containing oxytocin project to brain stem sites and to the intermediolateral cell column of the spinal cord-the site of the final common pathway for the sympathetic (visceral) efferent system. Although the details of this system are far from clear, the paraventricular nucleus would appear to be a site for the integration of neuroendocrine and autonomic mechanisms.

Levels of Integration in the Neuroendocrine System

Sites for regulating the response of specific functional adenohypophyseal cell populations and for integrating the responses of several populations of adenohypophyseal cells are found at several levels but understood well at only a few. At the level of the adenohypophyseal cell, feedback responsive to the level of peripheral target hormones occurs. For example, ACTH secretion is depressed by elevated cortisol levels. TSH secretion is depressed by elevated levels of thyroid hormone. Other hormones also regulate adenohypophyseal cell function. For example, epinephrine (from the adrenal medulla) stimulates ACTH secretion from corticotropes. The role of cytokines, produced locally or at a distance, in the regulation of adenohypophyseal function is only now being recognized. Adenohypophyseal secretions have a paracrine as well as an endocrine function and influence the function of neighboring adenohypophyseal cells as well as the secretion of distant targets. Adenohypophyseal cells also respond to neurosecretions from the median eminence and neural lobe, as the entire neurohypophyseal capillary bed serves as the final common pathway to the adenohypophysis. Specific releasing and inhibiting hormones regulate the activity of specific adenohypophyseal cell populations. Within the median eminence, there is a morphologic integration of separate neurosecretory systems to form functional regions. Reproduction is mediated laterally in the median eminence, whereas neurohormones involved in the regulation of the internal milieu, metabolism, and response to stress are segregated medially. Paracrine interactions between neighboring terminals are mediated by co-stored peptide hormones and transmitters. Such interactions are probably important in the modulation of hypophysiotropic hormone release. At the level of the hypothalamic nuclei, feedback mechanisms operate in the case of CRF-li and GnRH-li neurons, which respond to the levels of circulating steroid hormones. In addition, homotropic neurons synapse with themselves to make ultrashort feed­back loops. Synaptic connection between SRIF and GRH neurons suggests another type of reciprocal relationship. The organization of input into the hypothalamus is at this time dimly understood, and no organizing conceptual framework has been constructed.

Ascending catecholamine systems (with and without co-stored NPY) have been demonstrated to synapse with hypothalamic magnocellular and parvicellular neurosecretory neurons that secret AVP and CRH, respectively. This input is now known to be excitatory.

For the time being, the surgeon's scope of endeavour is limited to direct approaches to the pituitary to normalize its function. The understanding that releasing hormone systems do not require direct contact with their target cells and that these systems project toward the ventricular system in their transit from their sites of origin will permit investigation of the possibilities of transplanting the pituitary into the sella turcica or even into the ventricular system. Even transplantation of hypothalamic neurosecretory cell systems may be possible. Further clarification of the organization of the hypothalamus and of its input may make it possible to use stereotactic procedures to modify pituitary function. In the future it is to be expected that the pituitary surgeon will employ a broad range of procedures in the brain as well as in the pituitary gland to treat disorders of the neuroendocrine system.