General concepts of hypothalamus-pituitary anatomy
The hypothalamus is the part of the diencephalon associated with visceral, autonomic, endocrine, affective, and emotional behaviour. It lies in the walls of the third ventricle, separated from the thalamus by the hypothalamic sulcus. The rostral boundary of the hypothalamus is roughly defined as a line through the optic chiasm, lamina terminalis, and anterior commissure, and an imaginary line extending from the posterior commissure to the caudal limit of the mamillary body represents the caudal boundary. Externally, the hypothalamus is bounded rostrally by the optic chiasm, laterally by the optic tract, and posteriorly by the mamillary bodies. Dorsolaterally, the hypothalamus extends to the medial edge of the internal capsule (Fig. 2.1.1) (1).
The complicated anatomy of this area of the central nervous system (CNS) is the reason why, for a long time, little was known about its anatomical organization and functional significance. Even though the anatomy of the hypothalamus is well established it does not form a well-circumscribed region. On the contrary, it is continuous with the surrounding parts of the CNS: rostrally, with the septal area of the telencephalon and anterior perforating substance; anterolaterally with the substantia innominata; and caudally with the central grey matter and the tegmentum of the mesencephalon. The ventral portion of the hypothalamus and the third ventricular recess form the infundibulum, which represents the most proximal part of the neurohypophysis. A bulging region posterior to the infundibulum is the tuber cinereum, and the zone that forms the floor of the third ventricle is called the median eminence. The median eminence represents the final point of convergence of pathways from the CNS on the peripheral endocrine system and it is supplied by primary capillaries of the hypophyseal portal vessels. The median eminence is the anatomical interface between the brain and the anterior pituitary. Ependymal cells lining the floor of the third ventricle have processes that traverse the width of the median eminence and terminate near the portal perivascular space; these cells, called tanycytes, provide a structural and functional link between the cerebrospinal fluid (CSF) and the perivascular space of the pituitary portal vessels.
The conspicuous landmarks of the ventral surface of the brain can be used to divide the hypothalamus into three parts: anterior (preoptic and supraoptic regions), middle (tuberal region), and caudal (mamillary region). Each half of the hypothalamus is also divided into a medial and lateral zone. The medial zone contains the so-called cell-rich areas with well-defined nuclei. The scattered cells of the lateral hypothalamic area have long overlapping dendrites, similar to the cells of the reticular formation. Some of these neurons send axons directly to the cerebral cortex and others project down into the brainstem and spinal cord.
This region constitutes the periventricular grey of the most rostral part of the third ventricle. The preoptic periventricular nucleus surrounds the walls of the third ventricle and contains small cells poorly differentiated from the ependymal lining.
This region contains (midline to lateral) the paraventricular nucleus and its ventral expansion: the suprachiasmatic nucleus, the anterior hypothalamic nucleus, the lateral hypothalamic area, and the supraoptic nucleus. The paraventricular and supraoptic nuclei are prominent and highly vascularized. The cells of the paraventricular nucleus are densely packed and lie immediately beneath the ependyma of the third ventricle. They consist of several distinct cells groups, including a medial parvicellular group and a prominent magnocellular group. The supraoptic nucleus caps the optic chiasm and follows the optic tract laterally. This nucleus is composed mainly of uniformly large cells. Magnocellular components of both the supraoptic and paraventricular nuclei project fibres into the neural lobe of the hypophysis. Immunocytochemically, large cells in both nuclei contain either vasopressin (antidiuretic hormone (ADH)) or oxytocin, each of which is associated with a distinctive neurophysin. Regions of the paraventricular nucleus send axons to the brainstem and all levels of the spinal cord. The less differentiated central grey in the supraoptic region forms the anterior hypothalamic nucleus, which merges with the preoptic area. The suprachiasmatic nucleus constitutes a group of small round cells, dorsal to the optic chiasm. These neurons receive direct bilateral projections from the retina, and this connection provides the link between a cyclical environment and the internal clock.
Middle group (tuberal region)
The hypothalamus reaches its widest extent in the tuberal region, and the fornix separates the medial and the lateral hypothalamic areas. The medial portion contains three nuclei. The ventromedial nucleus occupies a strategic position in the hypothalamus and it has numerous afferent and efferent connections with many other regions of the CNS, including the brainstem. The dorsomedial nucleus is less distinct. Both nuclei are involved in autonomic function and emotional behaviour. The arcuate nucleus (infundibular nucleus) is situated in the most ventral part of the third ventricle and extends into the median eminence. This nucleus contains small cells that are in close contact with the ependymal lining. Axons from this nucleus form part of a diffuse projection system, the tuberoinfundibular tract, which terminates on the hypophyseal portal vessel system. This connection is of major importance to adenohypophyseal function.
Posterior group (mamillary region)
The posterior part of the hypothalamus consists of the posterior hypothalamic nucleus and the mamillary bodies. In humans, the mamillary body is a focal point for several prominent fibre bundles and it is formed by a large spherical medial mamillary nucleus containing small cells and surrounded by a capsule of heavily myelinated fibres. Lateral to this is the intermediate mamillary nucleus, with smaller cells, and even further laterally is a well-defined group of large cells, the lateral mamillary nucleus. The posterior hypothalamic nucleus is a large but poorly defined cell group that is continuous with the central grey matter of the mesencephalon. This nucleus consists of small and large cells. The latter are especially numerous in humans.
Rostrally and laterally, the hypothalamus is continuous with the basal olfactory region. Medially, this region extends dorsally, forming the so-called septal region, which is located beneath the rostral part of the lentiform nucleus and the head of the caudate nucleus. Beneath this region is a grey mass referred to as the substantia innominata, which contains clusters of large cholinergic neurons forming the basal nucleus of Meynert. Neurons in the basal nucleus constitute the major source of cholinergic innervation to the entire neocortex (2).
Major fibre systems
Due to its location at the base of the brain, access to the hypothalamus is limited in experimental investigations and thus it has been difficult to study the hypothalamic fibre connections. However, new tracing techniques have made this possible. The hypothalamus has extensive and complex connections with many regions in the forebrain, the brainstem and the spinal cord.
Several afferent neural pathways provide the hypothalamus with input from the forebrain, limbic system, visual cortex, thalamus, and brain stem.
Medial forebrain bundle
This is a widespread, loosely arranged system arising from basal olfactory regions and monoaminergic cell groups in the brainstem, the periamygdaloid region, and the subiculum. In its parasagittal course, this bundle receives contributions from the substantia innominata and the amygdaloid complex.
Hippocampus-hypothalamic fibres (fornix)
This is a large fibre bundle that originates in the hippocampal formation and projects to the septal area, the anterior thalamus, and the hypothalamus. This bundle can be exposed by dissection of the lateral wall of the third ventricle and followed to the mamillary body where many of its fibres terminate. In the septal region, the fornix forms two distinct bundles: the precommisural fibres, which are distributed to the septal nuclei, the lateral preoptic region, and the dorsal hypothalamic area; and the postcommisural fibres of the fornix, which project to the medial mamillary nucleus, except for those that leave this bundle to terminate in the anterior thalamic nuclei.
These fibres provides entry of emotional data from the amygdaloid nucleus into the hypothalamus. There are two different pathways: stria terminalis, which is the main pathway that connects the amygdaloid body and the medial hypothalamus, and the ventral-amygdalofugal fibres, which arise from the basolateral amygdaloid nucleus and extend to the lateral hypothalamic nucleus and medial forebrain bundle.
Brainstem reticular afferents
These fibres reach the hypothalamus through the mamillary peduncle of the lateral mamillary nucleu, and the ascending component of the dorsal longitudinal fasciculus from the central grey of the midbrain.
Cholinergic and monoaminergic pathways
The ascending cholinergic pathway, originating in the substantia nigra and ventral tegmental area, has widespread distribution in the forebrain, including the hypothalamus. The monoaminergic systems originating in the brainstem have a wide distribution in the forebrain and some of the projection systems, such as the mesolimbic dopamine pathway and the ventral ascending noradrenergic and the serotonergic pathways which pass through the lateral hypothalamic area. The ascending noradrenergic and the serotonergic systems distribute large number of fibres to the lateral and medial hypothalamus.
These fibres arise from ganglion cells of the retina and project bilaterally to the suprachiasmatic nuclei through the optic nerve and chiasm. These nuclei also receive inputs from the ventral and lateral geniculate nuclei and the paraventricular nuclei of the thalamus. This suprachiasmatic nucleus is well known as the pacemaker for circadian rhythms.
The hypothalamus receives connections from the posterior orbital cortex, pyriform cortex, cingulated gyrus, and the entorhinal cortex. In each instance, the cortical projection is reinforced by a corresponding subcortical projection. Both the sense of taste and the sense of olfaction are directly involved in arousal mechanisms and phases of consummatory behaviour. Gustatory pathways to the hypothalamus are multisynaptic, whereas olfactory projections to the hypothalamus are relatively direct.
These connections are partly reciprocal to the afferent systems. In addition, several efferent hypothalamic pathways have no counterpart among afferent systems. The medial forebrain bundle transmits impulses from the lateral hypothalamus to the hippocampal formation. The stria terminalis and the ventral pathway convey impulses from the hypothalamus to the amygdala. The dorsal longitudinal fasciculus carries descending fibres from the medial and periventricular hypothalamus to the midbrain and tegmentum. Mamillary efferent fibres arise mainly from the medial mamillary nucleus and quickly divide into two tracts: the mamillothalamic and the mamillotegmental tracts. The former projects to the anterior thalamic nuclei and the later terminates in the dorsal and ventral tegmental nuclei of the midbrain. It is not clear how the suprachiasmatic nucleus affects circadian rhythms, since its efferent projections are incomplete and do not reach the areas responsible for motor, autonomic or endocrine responses. Retrograde tracer injections in several hypothalamic areas have shown that suprachiasmatic nucleus sub-divisions into core and shell areas differ with respect to afferents, local connections, and neuroactive substances. The paraventricular nucleus and the lateral and posterior hypothalamus send fibres to the dorsal motor nucleus of the vagus, the medial solitary nucleus, and the nucleus ambiguous. These hypothalamic nuclei also send fibres to the spinal cord, which terminate in the intermediolateral cell column at all levels, influencing autonomic functions.
Hypothalamus and adenohypophysis (tubero-hypophyseal tract)
The anatomical basis for the hypothalamic control of the anterior lobe of the pituitary is complex. Neurosecretory cells in the arcuatus (infundibular) nucleus, the ventromedial nucleus, and the neighbouring regions produce releasing and inhibiting factors that regulate the secretion of hormones from the anterior lobe of the pituitary. The hormones reach the anterior lobe by axoplasmic transport through the axons of the tubero-infundibular tract and are then discharged into capillary loops in the median eminence. The hormones are then transported by the hypophyseal portal veins to a second capillary network in the anterior lobe, where they influence the secretion of the various adenohypophyseal hormones, such as thyroid-stimulating hormone (TSH), adrenocorticotropin hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone growth hormone, and prolactin. This tract arises mainly from the arcuate nucleus and ends in the median eminence and the infundibular stem. Fibres of the tubero-infundibular tract convey releasing hormones to the anterior lobe of the pituitary. Dopamine was the first substance identified in the arcuate nucleus; in the hypophyseal portal system it inhibits the release of prolactin from the anterior pituitary. A short feedback loop suggests that pituitary prolactin inhibits dopamine release from the median eminence. The arcuate nucleus also contains a number of peptides similar to hormones in the anterior pituitary, such as ACTH, β-lipotropin, and β-endorphin. These peptides do not appear to coexist in neurons with dopamine (3, 4).
The pituitary gland consists of an anterior lobe (adenohypophysis), a posterior lobe (neurohypophysis), and an intermediate zone. The adenohypophysis originates from the stomodeal ectoderm, which invaginates by the third week of gestation to form Rathke’s pouch. In the sixth week of gestation it comes into contact with the infundibulum. A remnant of the pharyngo-hypophysis is occasionally encountered in adults, forming the pharyngeal pituitary in the midline of the nasopharynx, which contains the full spectrum of pituitary hormones.
The first type of cell to develop in the human fetal pituitary is the corticotroph at 6 weeks in utero, follows by somatotrophs (8 weeks), thyrotrophs and gonadotrophs (12 weeks), and lactotrophs (after 24 weeks). Pituitary development and differentiation involve the sequential expression of several transcription factors, among which POU1F1 (PIT1) and PROP1 are the most important. Mutations in genes encoding these transcription factors can not only produce combined pituitary hormone deficiency (mainly growth hormone, prolactin, TSH, FSH, and luteinizing hormone) but also pituitary hypoplasia or agenesis. Tpit is a transcription factor that is essential for preventing differentiation of corticotrophs into other pituitary cell types. Mutations in the gene encoding Tpit cause congenital isolated ACTH deficiency.
The posterior portion of Rathke’s pouch gives rise to the intermediate lobe. This area normally contains microcystic remnants of Rathke’s pouch, which rarely are clinically significant. The neurohypophysis develops from a neuroectodermal bud in the floor of the diencephalon at 4 weeks of gestation. The portal system starts to develop at 7 weeks but is not completed until 18–20 weeks of gestation. The body of the sphenoid bone and the sella turcica result from fusion of hypophyseal cartilage plates on either side of the developing pituitary. The sella is well formed at 7 weeks and matures by enchondral ossification.
The pituitary gland is centrally situated at the base of the brain, in the sella turcica, within the sphenoid bone. It is attached to the hypothalamus by both the pituitary stalk and a fine vascular network. The sphenoid bone forms a midline slope (the tuberculum sella) and a transverse indentation (the chiasmal sulcus). The optic canals lie anterolateral to the sulcus, whereas the optic tracts are posterolateral. The floor of the sella forms a portion of the roof of the sphenoidal air sinus, which permits easy surgical access. The sloping anterior sellar wall gives rise to posterolateral projections, the anterior clinoid processes. Posterior to the sella, the sphenoid bone continues as the dorsum sella, forming the posterior clinoid processes. The pituitary lacks leptomeninges. The sella turcica is lined by periosteal dura mater whereas the dura proper covers the lateral aspects of the cavernous sinuses and constitutes the sellar diaphragm. Leptomeninges circle the stalk, below the level of the sellar diaphragm and reflect upon themselves forming the infradiaphragmatic hypophyseal cistern. There are individual variations in this regard, with examples where the leptomeninges form a large diaphragmatic opening. If such an individual undergoes transsphenoidal surgery, it may result in persistent CSF rhinorrhoea due to violation of the subarachnoid space.
There are a number of important vascular structures in the vicinity of the sellar region. The cavernous sinuses are on either side of the sella, lateral and superior to the sphenoid sinuses. Venous drainage to the sinuses is through the superior ophthalmic vein, inferior, and middle cerebral veins and the spheno-parietal sinus. Both cavernous sinuses communicate anteriorly and posteriorly to the sella, forming a complex venous ring. The cavernous sinuses represent extradural cavities, which comprise important neurovascular structures, including the cavernous segments of the internal carotid arteries, and the cranial nerves III, IV, V, and VI. Several branches of the internal carotid artery originate within the cavernous sinus, including the meningohypophyseal trunk, the artery of the inferior cavernous sinus, and small capsular branches. The meningohypophyseal trunk gives rise to several vessels, including the inferior hypophyseal artery, which supplies the posterior lobe and the pituitary capsule.
Vascular supply: hypophyseal portal system
The hypophysis is supplied by two sets of arteries that arise from the internal carotid artery. The superior hypophyseal artery forms an arterial ring around the upper part of the hypophyseal stalk; the inferior hypophyseal artery forms a ring about the posterior lobe and gives branches to the lower infundibulum. A single superior hypophyseal artery leaves each carotid shortly after its entry into the cranial cavity and soon divides into posterior and anterior branches, each of which anastomoses with the corresponding branch from the opposite side, to form an arterial ring around the upper pituitary stalk. The posterior and anterior branches of the superior hypophyseal arteries are the source of the ‘long stalk’ and ‘short stalk’ arteries. Branches of the inferior hypophyseal arteries supply the posterior lobe and lower portion of the stalk, sending small branches to the periphery of the anterior lobe. Some arterioles and capillaries in the pituitary stalk and infundibulum give rise to unique vascular complexes named ‘gomitoli’, which consist of a central artery surrounded by a glomeruloid tangle of capillaries. The transition between the central artery and the capillaries consists of specialized arterioles with thick smooth muscle sphincters that regulate the blood flow (Fig. 2.1.2).
The hypophyseal portal system originates from the capillary plexus of the median eminence and superior stalk, which is derived from the terminal ramifications of the superior and inferior hypophyseal arteries. This capillary plexus in the median eminence and superior stalk drains into the long portal vessels but runs along the stalk to supply largely the anterior lobe, whereas the smaller capillary plexus in the lower stalk gives rise to the portal vessels. The portal system communicates with the capillary network in the anterior lobe that carries hypophyseotropic factors into the pituitary and delivers anterior lobe hormones to the periphery. The venous drainage of the pituitary is via collecting vessels that drain in the subhypophyseal sinus, cavernous sinus, and superior circular sinus. The majority of the anterior lobe circulation is venous and originates from the portal vessels. However, the blood supply of the posterior lobe is arterial and direct, which explains the predilection of metastatic carcinomas for the neural lobe.
The anterior lobe comprises about 80% of the gland and includes the pars distalis, pars intermedia, and pars tuberalis. Staining characteristics help divide the pars distalis into a central ‘mucoid wedge’ and two ‘lateral wings’. On light microscopy the cells of the anterior lobe show variation in size, shape, and histochemical staining characteristics. They are organized in nests and cords, separated by a complex capillary network. This architectural pattern is altered in hyperplasia and adenomas (5, 6).
The pars distalis
Large numbers of cells in the central zone are basophilic and stain with periodic acid-Schiff (PAS) method. These cells produce ACTH, luteinizing hormone, FSH, and TSH. Most of the cells in the lateral wings are acidophilic and produce growth hormone or less frequently prolactin. Somatotrophs or growth hormone-secreting cells are present in greatest density in the lateral wings comprising approximately 50% of all adenohypophyseal cells. They are ovoid, medium size and with abundant acidophilic secretory granules. Pituitary somatotroph adenomas could be densely or sparsely granulated and the later is associated with aggressive tumours and worse response to therapy. Lactotrophs or prolactin-secreting cells comprise approximately 20% of anterior pituitary cells with wide variability related to age, sex, and parity in women. Lactotrophs are predominantly located in the posterior portions of the lateral wings. Histologically they are either acidophilic (densely granulated) or chromophobic (sparsely granulated). Densely granulated lactotrophs are thought to represent a storage phase, while sparsely granulated cells are associated with active secretion. A common feature of prolactin cells is their tendency to lie close to gonadotrophs, which is most likely due to a close physiological relationship. There are also mammosomatotroph cells producing prolactin and growth hormone. Prolactin cell adenomas could be densely or, more commonly, sparsely granulated.
Any space-occupying sellar or parasellar mass that compresses the pituitary stalk, impedes the principal hypothalamic prolactin-inhibitory factor delivery to the anterior lobe causing hyperprolactinaemia, a phenomenon termed ‘stalk effect’. Corticotrophs or ACTH-producing cells, comprise 15–20% of adenohypophyseal cells and are most numerous in the mid and posterior portions of the mucoid wedge. Histologically, ACTH cells are medium to large polygonal cell. The strong PAS positivity is related to a carbohydrate moiety present in proopiomelanocortin (POMC), which is the precursor of ACTH. Perinuclear bundles of cytokeratin filaments are also typical of ACTH cells. In the context of glucocorticoid excess, ACTH cells accumulate type I microfilaments (Crooke’s hyaline change). Thyrotrophs or TSH-secreting cells are located predominantly in the anterior part of the mucoid wedge, and represent approximately 5% of the adenohypophyseal cells. These are medium sized, elongated cells, which stain with basic dyes and are PAS positive. Gonadotrophs, or FSH and LH producing cells, represent about 10% of the pars distalis, are positive for basic dyes and PAS, and are evenly distributed throughout the anterior lobe. These cells have been shown to produce FSH and luteinizing hormone in isolation or by the same cell.
The pars intermedia (intermediate lobe)
This is very poorly developed in humans, and is formed by epithelial-lined spaces containing colloid; the cells are ciliated, goblet, and endocrine.
The pars tuberalis (also named pars infundibularis)
This is an extension of the anterior lobe along the pituitary stalk. It is formed by normal acini of pituitary cells distributed around surface portal vessels.
A different cell component in the anterior lobe is called follicular cell. These cells are derived from secretory cells and constitute follicles within the normal anterior pituitary. The folliculo-stellate cell is another unusual cell type that comprises less than 5% of the anterior lobe cells. These agranular cells are positive for S100 protein and their physiological role is unclear. These cells have been implicated in autocrine/paracrine regulation of anterior pituitary function, intrapituitary communication, and modulation of inflammatory responses.
The posterior lobe or neurohypophysis is a ventral extension of the central nervous system, where the hypothalamic hormones oxytocin and vasopressin are released. The neurohypophysis is composed of unmyelinated axons that originate from the supraoptic and paraventricular nuclei and from cholinergic hypothalamic neurones, a prominent vascular network and specialized glial cells named pituicytes. These cells are reactive for glial fibrillary acidic protein, an intermediate filament characteristic of astrocytes, and are in close association with neurosecretory fibres; their morphology varies considerably, ranging from astrocytic to ependymal, and their role is yet unclear. The most important function of the neurohypophysis is the transfer of hormonal substances from neurosecretory granules to the intravascular space and its complex anatomy constitutes the basis for this process.
The framework of hypothalamo–pituitary functioning
The current paradigm accepts that the hypothalamus controls the pituitary by the release of activating and inhibitory factors called neurohormones, which are produced by neurons and secreted in the median eminence. These neurohormones travel from the median eminence to the pituitary target cells via the portal vessels. Acting on pituitary cells, they cause or stop the secretion of the pituitary hormones; some of these hormones act directly on different tissues and others activate target glands (Box 2.1.1). The system integrates information and amplifies the action, the neurohormones integrate environmental and neural information and this is translated by a few molecules in a very limited vascular space, the portal blood vessels. In its turn, the pituitary integrates information coming from the CNS and the general hormonal information arriving from the rest of the body. This causes the pituitary hormones to be secreted in a meaningfu1 concentration in to the general vascular space (7, 8).
Growth hormone, also called somatotroph hormone, is mainly responsible for the physiological axial somatic growth and the general modulation of metabolism (Fig. 2.1.3). Growth hormone accounts for 10% of the net pituitary hormonal content. It is a single chain peptide molecule with several similarities to prolactin and placental lactogen, and is present in circulation and secreted in several isoforms. Growth hormone secretion occurs in pulses that occur every 3–4 h, the most pronounced discharge occurring during deep sleep or phases III–IV.
The somatotroph axis is based in three locations: hypothalamus, pituitary, and peripheral target tissues. The hypothalamic participation in the regulation of growth hormone secretion is exerted through two neurohormones, which reach the pituitary by the hypothalamo-pituitary portal vessels. One is growth hormone-releasing hormone (GHRH), which stimulates both synthesis and secretion of growth hormone, and the other is somatostatin, which inhibits the release, although not the synthesis, of growth hormone. In recent years it has been postulated that the endogenous ligand of the cloned growth hormone-secretagogue (GHS) receptor, i.e. ghrelin, may be implicated in the physiological regulation of growth hormone secretion, but this awaits definitive proof. Only after the full characterization of this third factor will it be possible to integrate it into a general framework of growth hormone regulation. Unlike other pituitary hormones, growth hormone does not have a target gland on which to operate, and its actions are exerted in a delocalized way over different peripheral tissues. Growth hormone exerts its action either directly or through the generation of insulin-like growth factor 1 (IGF-1) by the liver. Both growth hormone and IGF-1, by a feedback mechanism at hypothalamic and pituitary level, inhibit the further secretion of growth hormone. In contrast with other pituitary hormones, it is characteristic that growth hormone is powerfully regulated by peripheral signals such as thyroid and adrenal hormones, nutrients, and metabolites (see Fig. 2.1.3).
The biological action of GHRH is located in the first 28 amino acids, a fact being used to develop shorter analogues with diagnostic and therapeutic use. GHRH is abundant in splanchnic tissues, so circulating GHRH levels do not reflect the hypothalamic activity and are not usually measured for this purpose. Its determination has clinical utility only in ectopic tumours secreting GHRH causing acromegaly. The neurohormone somatostatin acting at the pituitary level inhibits the basal release of growth hormone as well as the growth hormone discharge elicited by all known stimuli. This action gave the name to somatostatin after its discovery, but later on other actions of the hormone became evident, such as inhibition of TSH, insulin, glucagon, and several other gastrointestinal hormones and functions. As somatostatin has abundant gastrointestinal distribution, it is not measured in the circulation in a clinical setting, because levels do not reflect hypothalamic activity. The significance of this widespread distribution and different actions, which are mediated by at least five types of receptors, are not clear. But the development of somatostatin analogues, with selective and powerful actions inhibiting GH and TSH secretion, have made possible their current use in clinical practice.
Except in tumoral hypersecretory states, GH secretion occurs in a pulsatile manner with eight to 12 pulses occurring in a 24-h period. Most of its daily output occurs during sleep (Fig. 2.1.4) especially in males. lt is currently believed that growth hormone pulses are generated by the interplay of the two antagonist hormones GHRH and somatostatin, and it has been suggested that for growth hormone to be released, GHRH and somatostatin secretion by the hypothalamus should be out of phase, an attractive mechanistic view that lacks, at present, definitive proof. This scheme of regulation has also been used to explain the growth hormone discharge induced by stress, physical exercise, arginine infusion, or drugs such as clonidine or pyridostigmine, as well as insulin-induced hypoglycaemia. Artificial compounds such as growth hormone-releasing peptide-6 (GHRP-6), hexarelin, and others collectively called GHSs, have been used as stimulants of growth hormone secretion, and for cloning their receptor; interestingly the endogenous ligand of this receptor has been discovered and named ghrelin. The nutritional and metabolic control of growth hormone secretion is remarkable. In fact, insulin-mediated hypoglycaemia, as in the classic insulin tolerance test (ITT), not only leads to a reflex discharge of growth hormone but also of prolactin, and ACTH/cortisol (Fig. 2.1.5). On the contrary, glucose administration inhibits growth hormone secretion, either basal or stimulated. A similar role is exerted by free fatty acids, the plasma reduction of which by pharmacological means enhances growth hormone secretion. On the contrary, their elevation by physiological or pharmacological means inhibits growth hormone secretion elicited by all stimuli so far known. Arginine and other amino acids stimulate the secretion of growth hormone by mechanisms that are still not well understood.
In summary, several physiological or pharmacological factors acting at hypothalamic level stimulate growth hormone secretion, namely deep sleep, hypoglycaemia, arginine, glucagon administration, physical exercise, clonidine, l-dopa, cholinergic agonists, and stress; others stimulate growth hormone, acting at the pituitary level, e.g. GHRH and free fatty acid reduction. On the contrary, growth hormone is reduced or inhibited by factors acting at the hypothalamic level, such as glucose load or cholinergic antagonists (atropine, pirenzepine) or at the pituitary level, such as somatostatin or free fatty acid rise.
Growth hormone actions
Growth hormone is rapidly cleared with a half-life between 10 and 20 min after its secretion into the circulation. Growth hormone circulates complexed to transporter proteins called growth hormone-binding proteins (GHBP), which are structurally equivalent to the extracellular region of the growth hormone receptor. The binding of growth hormone to the GHBP leads to a delayed clearance, but the physiological and pathological implications of such binding are at present controversial and it has not yet been ascertained whether variations in the growth hormone-GHBP complex may represent a new level of regulation in the somatotroph axis.
Acting at the liver, growth hormone generates IGF-1, which, either in free form or complexed to the several binding proteins, exerts widespread actions from which it is difficult to discern which are exerted by growth hormone and IGF-1. The main actions of growth hormone are the promotion of skeletal growth, mainly of long bones, and the regulation of several metabolic actions. In long bones growth hormone promotes growth by acting on the growing cartilage by a dual action, i.e. growth hormone initiates chondrocyte replication, which along with the maturative process, releases IGF-1 locally and expresses the IGF-1 receptor. This means that growth hormone initiates a local process, which is then propagated by the combined action of growth hormone and IGF-1. In the muscles, growth hormone acts as a trophic hormone, promotes the incorporation of amino acids and protein synthesis. On the contrary, at the adipose tissue level growth hormone promotes lipolysis and release of free fatty acids, exerting antagonistic actions on insulin.
With the availability of recombinant growth hormone, some previously unexpected actions of this hormone have been well defined. In this regard, growth hormone deficiency is clinically characterized by changes in body composition including increase in fat mass and reduction in lean mass, reduced muscular strength and exercise capability, as well as impaired psychological wellbeing, reduction in bone mineral density, alterations in lipoprotein and carbohydrate metabolism, and changes in renal and cardiac function. Growth hormone replacement reverses several of these adverse body composition changes. Recently, pegvisomant a bioengineered analogue of growth hormone, which blocks growth hormone receptor, has been developed. Pegvisomant inhibits IGF-1 synthesis and reverses most of the morbid consequences of growth hormone excess.
The reduction in growth hormone levels that occurs with progressive ageing may be in part responsible for the deleterious changes in body composition associated with ageing (see also Chapter 2.3.7).
ACTH is a single chain peptide released by specific cell types of the pituitary, the corticotroph cells. The initial synthesis is of a larger peptide called POMC, which after proteolytic cleavage generates several peptides and hormones, among which are ACTH, and β-lipotropin. The main role of ACTH is to stimulate synthesis and secretion of the adrenal cortex hormones, mainly cortisol. ACTH is secreted in a pulsatile fashion, which is under positive hypothalamic control through a neurohormone called corticotropin-releasing hormone (CRH), which acting on specific pituitary receptors, increases ACTH secretion and POMC gene expression (Fig. 2.1.6). Direct evidence for a regulatory role of factors other than CRH is absent in human. Levels of ACTH and cortisol follow a circadian rhythm with higher values in the first hour of the morning (06.00–08.00 h) that become progressively reduced, reaching the nadir (approximately 50% of morning levels) at around 20.00 h (see Fig. 2.1.4). This circadian rhythm is generated in the suprachiasmatic and paraventricular nucleus of the hypothalamus. Superimposed onto the circadian rhythm and at any time, a stressful situation, either physical or mental, may induce a large discharge of ACTH into the circulation with a similar increase in cortisol; this stress-mediated release is more robust if the stressful situation is unexpected. Apart from the above situations, the system is maintained under equilibrium by the feedback regulatory action of cortisol, which acting mainly on the pituitary and also on the hypothalamus, inhibiting or reducing ACTH release. A classic regulatory feedback is established between ACTH and cortisol, and the role of CRH is to determine the set point of the system, to modulate the circadian rhythm and, in case of stress, to start a stress response. The biological variable to be maintained is cortisol, and the other adrenal cortex hormones whose secretions are enhanced by ACTH, such as androgens, do not exert a regulatory feedback action at the pituitary. This explains why in situations of enzymatic defects that selectively lead to a reduced cortisol secretion, overstimulation exerted by ACTH normalizes cortisol levels at the expense of hypertrophy of the adrenal glands, thereby inducing different degrees of virilization due to androgen oversecretion. ACTH has no biological actions other than stimulating the adrenal cortex; therefore the clinical manifestations of its abnormal secretion will be those of either excess or reduced secretion of adrenal hormones, mainly cortisol. The system is exquisitely regulated and the simultaneous evaluation of ACTH and cortisol is valuable. On a theoretical basis, a deficit in cortisol secretion with elevated ACTH levels (also elevated melanocyte-stimulating hormone levels, and then skin hyperpigmentation) is indicative of an adrenal defect (Addison’s disease), and the same cortisol deficit with normal or low ACTH levels (no pigmentation) suggests ACTH deficiency. However, in most cases dynamic or provocative tests are needed to firmly establish the diagnosis.
The negative feedback of cortisol on the ACTH secretion by corticotrophs may be imitated by synthetic glucocorticoids such as dexamethasone. As tumorous corticotrophs are more resistant to this feedback than normal ones, this fact has been exploited in the differential diagnosis of Cushing’s syndrome. A low dexamethasone dose able to reduce ACTH secretion and then cortisol levels in healthy people will fail in the case of a pituitary adenoma secreting ACTH (Cushing’s disease). A high dose of dexamethasone will usually overcome the resistance of the pituitary adenoma inhibiting ACTH and cortisol, but will not suppress the hypercortisolism of an adrenal adenoma, which is associated with low ACTH levels.
The neurons secreting gonadotropin-releasing hormone (GnRH) into the arcuate nucleus of hypothalamus are modulated for many neurotransmitters and peptides from various brain regions and also by environmental and hormonal signals. GnRH neurons may have an intrinsic pulse-generating capacity and they secrete and release GnRH in a pulsatile manner. This GnRH pulsatility is essential for maintenance of normal gonadotropin pulsatile secretion and gonadal steroids synthesis, which in turn exert both stimulatory and inhibitory actions at the hypothalamic level.
Kisspeptins are a family of peptides that act through the specific G-protein-coupled receptor (KISS1) to markedly stimulate GnRH-induced gonadotropin secretion. Mutations in the gene coding for this receptor, result in idiopathic hypogonadotropic hypogonadism. Kisspeptin–KISS1 signalling has an important role in initiating GnRH secretion at puberty. Levels of gonadotropins are very low in children but are already pulsatile in prepuberty. In females, GnRH pulsatility controls the activation of the reproductive system as well as its deactivation. In prepuberty, very low plasma gonadotropin values increase progressively and the pulsatile pattern is mainly nocturnal. These changes are accentuated in puberty. In women the pulsatile pattern of gonadotropins is regarded as a reflection of the rhythm induced by GnRH secretion, with the difference that an external increase in the frequency or quantity of GnRH leads to receptor desensitization and to the paradoxical inhibition in the release of gonadotropins. This fact is used in the clinical setting for inducing a reversible chemical castration by the administration of large doses of exogenous GnRH.
The hypothalamic control of luteinizing hormone and FSH secretion is extremely sensitive to environmental conditions such as stressful situations and to changes in nutrition or energy homoeostasis (Fig. 2.1.7). It is assumed that stress activates the intrahypothalamic corticotropin-releasing hormone pathways, which would inhibit the GnRH neurons through opiate pathways. Mental or psychological stress, such as changing home, or problems at work, or alternatively a relevant reduction in the daily food intake leads to a reduction in GnRH secretion translated into a reduced and non-pulsatile secretion of luteinizing hormone and FSH in the circulation. In fact, in patients with malnutrition-mediated amenorrhoea, such as in anorexia nervosa, gonadotropins return to the prepubertal pattern.
In the follicular phase most of the luteinizing hormone pulses are followed by a release of oestrogens from the ovary, and in the mid and late luteal phase the luteinizing hormone pulses induce a progesterone secretion. Oestradiol and progesterone exert an inhibitory action on the release of luteinizing hormone, acting at both hypothalamic and pituitary level; however, in the follicular phase associated with an enhanced release of oestradiol the inhibitory action suddenly changes to a stimulatory one, inducing a large discharge of luteinizing hormone, which is responsible for ovulation (see Fig. 2.1.7). The ovary exerts negative feedback on FSH secretion mostly through the secretion of the peptide hormone inhibin, which is synthesized in granulosa cells of the ovarian follicle and counterbalanced by activin. In the late follicular phase inhibin levels increase and, in combination with oestradiol, inhibit the synthesis and release of FSH, an inhibition that is overcome at the preovulatory gonadotrophin discharge. The regulation of the gonadal axis is equally complex but more static in males. No clear data regarding the regulation of GnRH by stress, or nutrition exist in males (Fig. 2.1.8). It is assumed that gonadotropin pulses in males follow the scarce pulses of hypothalamic GnRH and in fact are highly variable and of small amplitude. Unlike in females, the luteinizing hormone pulses are not translated into a peripheral pulse of testosterone, and no positive feedback on luteinizing hormone secretion has been reported, the system being operative on simple negative feedback. Sertoli cells in the male secrete activin and inhibin in order to regulate FSH secretion.
The axis is regulated at three levels and the hypothalamic participation is exerted through the synthesis and release in the median eminence, and hence in the portal vessels, of thyrotropin-releasing hormone (TRH). Acting through specific receptors on thyrotroph cells, TRH induces the secretion of TSH, which in turn activates follicular cells in the thyroid gland to secrete into circulating blood the thyroid hormones triiodothyronine (T3) and thyroxine (T4). Thyroid hormones act on practically all tissues of the body, exerting multiple functions but mainly on general metabolic homoeostasis. Acting on the pituitary gland, they exert a negative feedback on thyrotrophs, inhibiting the release of TSH thereby closing the regulatory circuit (Fig. 2.1.9). They also act at hypothalamic level to reduce TRH secretion but this action is at best ancillary.
TSH secretion follows a circadian rhythm with elevation in the late hours of the evening (see Fig. 2.1.4). In addition to thyroid hormones, it is under the negative control of dopamine and somatostatin, and under the positive control of oestrogens. The physiological meaning and relevance of these regulations is controversial. The inhibitory action of somatostatin on TSH secretion is currently used employing somatostatin analogues in clinical practice to control pituitary tumours that secrete TSH. Between the two messages arriving at the pituitary thyrotroph cell, the stimulatory message of TRH and the inhibitory one of the thyroid hormones, the latter is more powerful. In fact, the administration of exogenous TRH to elicit a TSH discharge becomes dampened or blocked in situations of hyperthyroidism and is enhanced in hypothyroidism.
The main action of prolactin is to initiate and maintain physiological lactation (Fig. 2.1.10). Released by lactotroph cells of the adenohypophysis, its molecular structure is similar to growth hormone and placental lactogen and they share a common phylogenetic origin. Similar to growth hormone, prolactin is a pituitary hormone acting on peripheral tissues without the intervention of a target gland.
The hypothalamic tubero-infundibular dopaminergic system is the main regulator of prolactin secretion. Among the pituitary secreted hormones, prolactin is the only one with a negative hypothalamic control through dopamine. This fact confers some peculiarities to prolactin regulation and in cases of pituitary stalk section, prolactin secretion may be maintained, and when the hypothalamo-pituitary connection is impeded, all pituitary hormones are reduced except for prolactin. Dopamine reaches the lactotrophs through the hypothalamic-pituitary portal system and inhibits prolactin release. Dopamine is the only widely accepted physiological regulator of prolactin secretion. Hypothalamic stressors such as the insulin tolerance test (ITT) are able to release prolactin, and exogenous administration of TRH releases prolactin in addition to TSH, operating through specific lactotroph receptors. Both tests have been used for assessing the pituitary reserve of prolactin but they are not considered to be physiological regulators of its secretion.
Prolactin is secreted in a pulsatile fashion with a rhythm that shows an enhanced nocturnal secretion not associated with specific sleep stages (see Fig. 2.1.4). Nonspecific stress is able to release prolactin in some individuals, a fact that must be taken into account in clinical testing. Oestrogens have a marked effect on lactotroph cells, producing hyperplasia as well as enhanced prolactin secretion. The increment in pituitary volume in pregnant women may be in part due to the large oestrogenic production by the fetoplacental unit. Lactation and sexual intercourse increase prolactin secretion, and hypothyroidism in both genders is able to increase prolactin secretion through an unexplained mechanism; perhaps due to the hypersecretion of TRH by the thyroid hormone-deprived hypothalamus plus enhanced TRH receptor expression in lactotrophs.
Abnormally elevated levels of prolactin are capable of altering several endocrine axes in both sexes, inducing different degrees of hypogonadism. However the physiological role of this hormone is only accepted in pregnant or lactating women. Prolactin is viewed as the hormone that induces the maternal instinct. In mammary tissue primed with oestrogens and progesterone, prolactin induces the synthesis of milk proteins. After partum, the stimulation on the mammary nipple during lactation induces a nervous signal, which on reaching the hypothalamus inhibits dopamine secretion, releasing prolactin, which in turn stimulates milk production. Oxytocin, which is released simultaneously, ejects the accumulated milk.
The hypothalamus through specific neurohormones controls the release and action of several pituitary hormones that play a leading role in endocrine physiology. Hypothalamic hormones are not commonly measured in blood, but are injected for diagnostic testing. On the contrary, pituitary hormones and their target peripheral hormones are commonly measured in the clinical setting. Except ITT, the most provocative tests of pituitary secretion, such as the administration of GnRH, GHRH, and TRH, are less commonly used and have been replaced by the analysis of pituitary hormone basal value weighted against the peripheral hormone.
1. Kovacs K, Scheithauer BW, Horvath E, Lloyd RV. The World Health Organization classification of adenohypophyseal neoplasms. Cancer, 1996; 78: 502–10.
Find This Resource
2. Nieuwenhijzen Kruseman AC. Structure and function of the hypothalamus and pituitary. In: Grossman A, ed. Clinical Endocrinology. 2nd edn. Oxford: Blackwell Science, 1998: 83–9.
Find This Resource
3. Nieuwenhuys R. Chemoarchitecture of the Brain. Berlin: Springer-Verlag, 1985.
Find This Resource
4. Clemmons D, Robinson I, Christen Y. IGFs: Local repair and survival factors throughout life span. 1st Edition; 2010, XIII, 157 p.
Find This Resource
5. Casanueva FF, Molitch ME, Schlechte JA, Abs R, Bonert V, Bronstein MD, et al. Guidelines of the Pituitary Society of the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf), 2006; 65(2):265–73.
Find This Resource
1. Couce M, Dieguez C, Casanueva FF. Pituitary anatomy and physiology. In: Wass JAH, Shalet SM, eds. Oxford Textbook of Endocrinology and Diabetes. Oxford: Oxford University Press, 2002: 75–85.
Find This Resource
2. Anderson E, Haymaker W. Breakthroughs in hypothalamic and pituitary research. Prog Brain Res, 1974; 41: 1–60.
Find This Resource
3. Carpenter MB. Core Text of Neuroanatomy. 4th edn. Baltimore: Williams and Wilkins, 1991; 297–324.
Find This Resource
4. Heimer L. The Human Brain and Spinal Cord. Functional Neuroanatomy and Dissection Guide. NewYork: Springer-Verlag, 1983: 296–307.
Find This Resource
5. Bevan JS, Scanlon MF. Regulation of the hypothalamus and pituitary. In: Grossman A, ed. Clinical Endocrinology. 2nd edn. Oxford: Blackwell Science, 1998: 90–112.
Find This Resource
6. Leakk RK, Moore RY. Topographic organization of suprachiasmatic nucleus projecting neurons. J Comp Neurol, 2001; 433: 312–34.
Find This Resource
7. Casanueva FF. Enfermedades del hipotalamo y la adenhipofisis. In: Rozman C, ed. Medicina Interna Textbook. Vol. 11. 16th edn. Barcelona: Harcourt, 2008: 2028–54.
Find This Resource
8. Sam S, Frohman LA. Normal physiology of hypothalamic pituitary regulation. Endocrinol Metab Clin North Am, 2008; 37: 1–22.
Find This Resource