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The pituitary is an organ of dual origin. The anterior part (adenohypophysis) is derived from oral ectoderm and is epithelial in origin, whereas the posterior part (neurohypophysis) derives from neural ectoderm. The mixed embryological derivation of the pituitary gland requires that developmental signals from both the neural and oral ectoderm must interact temporally and spatially to control maturation of the pituitary gland and the cellular differentiation of the various hormone-producing cell types within the adenohypophysis. The expression of transcription factors that control cell lineage commitment in the developing adenohypophysis must be regulated precisely to ensure correct differentiation of hormone-producing cell types; the iterative and cumulative nature of this regulation renders it extremely sensitive to perturbation. Disruption of this process, for instance by mutation, can lead to numerous developmental disorders from congenital forms of hypopituitarism to pituitary tumors ()().

Pituitary organogenesis begins during week 4 of fetal development. A thickening of cells in the oral ectoderm forms the hypophyseal placode which gives rise to Rathke’s pouch; an upward evagination of the buccal ectoderm that extends towards the neural ectoderm. At the same time, a downward extension of the ventral diencephalon forms the posterior lobe, and the two nascent lobes connect to form the bilobed structure of the adult pituitary gland. Rathke’s pouch constricts at its base and eventually separates altogether from the oral epithelium during gestational week 6-8. The cells of the anterior wall of Rathke’s pouch undergo extensive proliferation to form the anterior lobe. In humans, the posterior wall proliferates more slowly to form the vestigial intermediate lobe (). Cell patterning and terminal differentiation occurs within the anterior lobe to form the five principal specialized endocrine cell types of the pituitary gland; the somatotrophs, adrenocorticotrophs, gonadotrophs, thyrotrophs, and lactotrophs.

Development of the pituitary occurs broadly in three stages: Initiation of pituitary organogenesis and formation of Rathke’s pouch (Blue in Supplementary Table). Evagination of Rathke’s pouch and cell proliferation (Green in Supplementary Table). Lineage determination and cellular differentiation (Yellow in Supplementary Table). Much of our understanding of the process of pituitary organogenesis comes from mouse studies ()(), but the phenotypes associated with human disorders often share aspects with mouse models of defective pituitary development. Various transcription factors that are involved are presented in and summarized in ()()()().

Significant advances have been made in recent years in elucidating the molecular mechanisms underlying the commitment and differentiation of Rathke’s pouch progenitors and the role of endocrine stem cells in the adenohypophysis ()(). Many factors are involved in pituitary differentiation, but a few later acting transcription factors have pituitary-specific effects and have become clinically relevant (). In clinical terms, cells of the adenohypophysis can be divided into those of the Pit-1 lineage (somatotrophs, lactotrophs, somatomammotrophs, and thyrotrophs), those of t-PIT lineage (corticotrophs and melanotrophs), and those of SF-1 lineage (Gonadotrophs).

PIT-1 was first identified as a trans-activating factor of the growth hormone and prolactin genes. It is a member of the POU homeodomain family of transcription factors (). Inactivating mutations produce recessive hypopituitarism characterized by a congenital lack of growth hormone, prolactin and TSH (). Two naturally occurring recessive mouse mutants have Pit-1 defects; the Snell Dwarf ( dw ) mouse and the Jackson dwarf ( dwJ ). Homozygous recessive variants of these mice both exhibit post-natal, but not embryonic, anterior pituitary hypoplasia with GH, PRL and TSH deficiencies.

t-PIT (TBX19) is a member of the T-Box family of transcription factors. The T-Box represents the DNA binding domain of these factors. T-Pit is expressed in the developing pituitary and expression generally persists into the adult gland. T-Pit depletion in mice induces severe ACTH and glucocorticoid deficiencies in addition to adrenal hypoplasia and pigmentation defects. The phenotype of t-Pit -/- mice suggests that T-PIT promotes the development of corticotrophs but can also actively repress gonadotroph formation ().

SF-1 is a nuclear receptor encoded by the gene Nr5a1 or steroidogenic factor 1 ( SF-1 ). It is an orphan nuclear receptor involved as a transactivating factor in steroid biosynthesis. SF-1 is expressed throughout the adrenal and reproductive axes during development and postnatal life ()(). Mutations of SF-1 in humans are associated with 46XY sex reversal with adrenal failure, 46XY gonadal dysgenesis and 46XX ovarian insufficiency and premature ovarian failure ()().

In some cases, transcription factor deficiency does not result in the complete absence of a cell type. SF-1 deficient mice do not spontaneously produce gonadotrophins but hyperstimulation with GnRH can induce hormone production suggesting that SF-1 is not essential for gonadotroph differentiation (). Similarly, t-Pit expression is not essential for corticotroph development, but POMC synthesis is delayed if they are deficient (). The failure to promote differentiation along a particular lineage can be permissive for other pathways and the idea that single transcription factors direct cell differentiation is overly simplistic. Nevertheless, these differentiation markers (colored blue in ) have proven to be extremely useful in diagnostic pituitary pathology, particularly in demonstrating the cell lineage of silent or non-expressing pituitary adenomas, and their expression can be detected in histological samples of pituitary tissue removed at trans-sphenoidal adenohypophysectomy by immunohistochemistry ().

The mature pituitary gland, or hypophysis cerebri, is a small, oval body weighing approximately 0.5g. The adenohypophysis of the pituitary is generally smaller in men than women and, within the female population, the gland in nulliparous women is generally smaller than that seen in multiparous women ()(). Indeed, during pregnancy, the gland may increase by approximately 30% due to a combination of lactotroph hyperplasia and vascular engorgement. The hypophysis is connected to the brain via the infundibulum, a tubular structure arising from the tuber cinereum and median eminence of the hypothalamus. The gland rests in the sella turcica (pituitary fossa) of the sphenoid bone and is covered superiorly by the diaphragma sellae (a thin film of dura), laterally by the walls of the cavernous sinus, and antero-inferiorly by the posterior wall of the sphenoid sinus; the latter used as the standard route for pituitary surgery or transsphenoidal adenectomy (). Antero-superiorly, the pituitary lies in close proximity to the optic chiasm and bilateral, inferomedial compression of the chiasm by the expanding gland explains why space-occupying lesions of the pituitary commonly present with bitemporal hemianopia. Inferiorly, the adenohypophysis is separated from the floor of the sella turcica by a large, loculated venous sinus that communicates with the circular sinus.

The structure of the hypothalamus and its complex connections are well known and have been described in detail elsewhere ()()(). The hypothalamic nuclei that give rise to the neurohypophysis arise from the preoptic, supraoptic, lateral, tuberal and mamillary regions () and hypothalamic regulatory neurons have their cell bodies in the supraoptic, paraventricular, infundibular and ventromedial nuclei of the hypothalamus. These hypothalamic nuclei have projections that terminate throughout the median eminence, infundibulum, and the posterior lobe (). Neurons derived from hypothalamic nuclei produce peptidergic “releasing hormones” that are transported along axons and released into the portal system from where they are carried to the dense capillary plexus of the adenohypophysis to influence hormone synthesis and release. The parvocellular neurosecretory pathway of the tuberoinfundibular tract is proposed as the main route for the synthesis of releasing hormones and of transmission to portal blood. The major trophic factors originating in the hypothalamic nuclei include growth hormone releasing factor (GRF), corticotrophin releasing factor (CRF), thyrotropin releasing factor (TRF), gonadotrophin releasing hormone (GnRH) and other peptides such as somatostatin (SS). Other trophic and inhibitory factors are also released in this region including dopaminergic compounds.

In addition to nerve fibers, the long and short portal blood vessels (distributed between sinusoids in the median eminence, infundibulum, and the adenohypophysis) are also of major importance to this region. The adenohypophysis receives no major nerve supply and almost all of its blood comes from hypothalamic-hypophysial portal vessels. The predominant direction of blood flow is from the tufts of sinusoids in the median eminence and infundibulum via the portal vessels to sinusoids between glandular cells in the anterior lobe. This neurovascular arrangement is of vital importance to understand the mechanism by which the hypothalamus regulates the neuroendocrine function of the gland. Neurosecretion is the physiological process involved in the production and release of posterior lobe oxytocin and vasopressin and their related proteins: including the precursor neurophysins. In terms of these magnocellular neurosecretory pathways, both the supraoptic and paraventricular nuclei are involved in the production both of vasopressin and oxytocin, however, vasopressin originates predominantly from the supraoptic nucleus and oxytocin originates predominantly from the paraventricular nucleus.

The infundibular stalk is a tubular, funnel-shaped structure divided into the anterior pars tuberalis and posterior pars infundibularis . The pars tuberalis is considered to be part of the adenohypophysis (see below) and contains a few scattered gonadotroph or corticotroph cells. Anteriorly and superficially, it surrounds the pars infundibularis (infundibular stem), which contains the unmyelinated axons of the magnocellular supraoptic and paraventricular neurons. The neurons contain large intra-axonal accumulations of oxytocin and vasopressin that may be seen as eosinophilic ovoid granular swellings along the trajectory of these axons in the infundibular stem. These ovoid swellings are known as “Herring bodies” named after Percy Theodore Herring who first described them (). It also contains the neural connections of the hypophysis that are continuous with the median eminence of the tuber cinereum.

The adenohypophysis comprises the vast majority of the pituitary gland by volume and is composed of three parts: the pars distalis , the pars intermedia and the pars tuberalis . The pars distalis forms the majority of the adenohypophysis, the pars intermedia is rudimentary in the human but represents the vestigial posterior limb of Rathke’s pouch and the pars tuberalis is an upward extension of the adenohypophysis that surrounds the lower regions of the hypophysial stalk. The anatomy of this region is shown in .

The pars distalis of the adenohypophysis is a highly vascular structure, consisting of epithelial cells of varying size and shape arranged in cords, irregular masses or follicles, separated by thin-walled vascular sinusoids and supported by a complex network of reticular tissue best appreciated in reticulin preparations (). This region of the adenohypophysis contains several cell types, generally divided into acidophils and basophils (depending on their staining properties with mixed acidic and basic dyes such as Orange-G/aldehyde fuchsin, (). These cells release trophic hormones including growth hormone (GH), prolactin (PRL), adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH) and luteinizing hormone (LH). The regulation and production of these trophic hormones is complex and is thought to be the result of a combination of the release of hypothalamic releasing factors into the median eminence, the regulation of portal blood flow by vascular systems, feedback by systemic hormones, autocrine interactions and complex paracrine interactions within the gland ()()().

The cellular heterogeneity within acini may be demonstrated tinctorially in PAS-OG preparations (, ) which were widely used before the adoption of antibody-based stains (). Corticotroph cells are generally strongly basophilic (PAS-positive), somatotroph and lactotroph cells mostly acidophilic (orangeophilic), whilst gonadotrophs and thyrotrophs may be basophilic or chromophobic (reacting with neither acid nor basic stains). There is no perfect match of hormone-expression and type or degree of chromophilia; some chromophobe cells may represent degranulated chromophil cells or precursor cells. In a normal adult adenohypophysis, approximately 10% of endocrine cells are basophils, 40% acidophils and 50% chromophobes.

The PAS-OG stain is still a useful supplementary method in the differential diagnosis of some pituitary lesions (hyperplasia, corticotroph microadenoma, Crooke’s cell changes or adenoma) but these tinctorial stains have all largely been replaced by immunohistochemical methods (). Although most acini contain a mixture of different hormone-producing cells, there is evidence of zonation (). The lateral wings of the gland mostly contain somatotrophs and lactotrophs, whilst corticotrophs are concentrated in the median mucoid wedge, which at its anterior border (the rostral tip) harbors clusters of thyrotrophs. Gonadotroph (LH/FSH) cells are diffusely scattered throughout the gland.

Somatotrophs represent about 50% of cells in the adenohypophysis and are located predominantly, but not exclusively, in the lateral wings. They are readily identified by the expression of growth hormone. A subset of somatotrophs also express the common glycoprotein hormone alpha-subunit. They are the second cell type to form during fetal development and are detected by 8 weeks of gestation.

Lactotrophs express prolactin. The number of prolactin-secreting cells varies widely between the sexes and with parity. The Golgi apparatus is well developed in lactotrophs and contains immature, pleomorphic secretory granules. Granule extrusions are common in lactotrophs, not only at the basal cell surface, but also on the lateral cell borders; the latter is a distinctive feature of lactotrophs seen on electron microscopy and is known as “misplaced exocytosis”. Lactotrophs appear to arise from mammosomatotroph cells and pure lactotrophs appear late in gestation (24 weeks). The expansion and secretion of lactotrophs is controlled by exogenous hormones including estrogen, paracrine effects from adjacent adenohypophysial cells and inhibitory substances from the hypothalamus.

These bihormonal cells contain both growth hormone and prolactin. Mammosomatotrophs are the precursors of lactotrophs and, as in lactotrophs, misplaced exocytosis can be seen on electron microscopy (). These cells are thought to be the source of lactotroph increases during pregnancy ().

Corticotrophs synthesis the molecule pro-opiomelanocrortin (POMC) which is cleaved post-transcriptionally to produce bioactive peptides including adrenocorticotrophic hormone (ACTH), melanotrophin (MSH) lipotrophic hormone (LPH) and endorphins (). These cells comprise about 15-20% of the cell component of the adenohypophysis and the cells are concentrated in the central mucoid wedge. They are best identified histologically by using antibodies raised against ACTH. Corticotrophs are the first cell type to differentiate in the fetal pituitary gland at 6 weeks of gestation and ACTH can be detected at 7 weeks. Exposure to glucocorticoid access, either by exogenous corticosteroid administration or any cause of endogenous glucocorticoid hypersecretion, including ectopic secretion of ACTH, causes corticotrophs to undergo a distinctive, but reversible, morphological alteration known as Crooke hyaline change ().

These are the most infrequent cell type within the adenohypophysis and are detected by the expression of the glycoprotein hormone common alpha-subunit and the beta-subunit of TSH. This can be demonstrated by immunohistochemical double labelling for both subunits. Thyrotrophs are detectable at about 12 weeks of gestation.

Gonadotrophs produce both luteinizing hormone (LH) and follicle stimulating hormone (FSH) and both hormone specific beta-subunits and the common alpha-subunit can be detected in these cells. Gonadotrophs are scattered throughout the pars distalis and are the major constituent of the pars tuberalis. Gonadotrophs are intimately associated with lactotrophs and electron microscopy reveals gap junctions between them. The synthesis and release of the gonadotrophins is differentially regulated by the hormonal milieu, paracrine interactions and the pulsatile frequency of GnRH ()(,). There is growing evidence that the precise control of pituitary gland secretion also involves a contribution from cells with the capacity to demonstrate plasticity with self-renewal and it is likely that the pituitary contains a pool of stem cells ()()()(). It is possible that these stem cells, possibly expressing Nestin, Lhx3 and Sox2, may exhibit self-renewal properties and have the ability to differentiate into different hormone-producing cell types in response to differing physiological demands ()()().

Folliculostellate (FS) cells are (in the adult human pituitary) an agranular (non-hormone-producing) parenchymal component of the pars anterior. It has been postulated that they represent a stem cell capable of trans-differentiation into endocrine cells (), but whether this is true in humans is not certain. FS cells are small, chromophobe, with slender processes that extend between the endocrine cells. They form small follicles at the center of acini, comprised of apical tips of multiple FS cells. They may be visualized with antibodies raised against the S100 protein and GFAP, but their expression pattern is not always overlapping and may reflect different stages of maturation or function. In our hands, annexin-1 immunohistochemistry is a robust marker of FS cells (). Annexin 1 (ANXA1) is a member of the annexin family of phospholipid- and calcium-binding proteins. ANXA1-positive FS cells may modulate glucocorticoid feedback loops in the anterior gland (){John, 2006 #340;John, 2006 #340}1)() or act as antigen-presenting cells. FS cells are also postulated to play a role in paracrine regulation (,).

The pars tuberalis is characterized by a large number of traversing vessels. Between these are cords or balls of undifferentiated cells admixed with acidophilic and basophilic cells. The secretion of adenohypophyseal hormones into the circulation appears to occur by exocytosis of the vesicular contents into the perivascular spaces of the sinusoids, the latter being lined with a fenestrated endothelium which facilitates diffusion into the bloodstream. The signal for secretion is the liberation of chemical releasing factors from neurons in the median eminence, and other hypothalamic centers, into the portal system of veins by which they are carried and distributed within the adenohypophysis.

In contrast to rodents, the pars intermedia is rudimentary in adult humans (). It represents a narrow zone between the adeno- and neurohypophysis often containing microscopic remnants of Rathke’s cleft. This zone may also contain scattered intensely PAS-positive corticotrophs, which may extend from the mucoid wedge of the adenohypophysis into the neurohypophysis. This so-called “basophil invasion” must not be confused with corticotroph microadenomas; it is believed to increase with age, and it has been suggested that these basophil cells are functionally distinct from classical ACTH-producing cells of the adenohypophysis and do not respond with hyaline degeneration (“Crooke’s cell change”) in the setting of systemic hypercortisolemia. Secretory cells of the pars intermedia have granules containing either alpha- or beta-endorphin; these cells have been shown to contain various peptide hormones including ACTH and alpha-MSH (melanocyte stimulating hormone).

The neurohypophysis does not contain neuroendocrine epithelial cells. Instead, it is composed of the axons arising from groups of hypothalamic neurons, most prominently those originating from magnocellular neurons of the supraoptic and paraventricular nuclei (). Some of these axons are short and terminate in the median eminence and infundibular stem among the superior capillary beds of the venous portal circulation. Longer axons pass into the main neurohypophysis thereby forming the neurosecretory hypothalamo-hypophyseal tract with their terminals ending near the sinusoids of the posterior lobe. These neurosecretory granules mostly contain oxytocin or vasopressin and form axonal beads close to their termini. Whilst it is believed that normal astrocytes may populate (at least partially) the infundibulum, the axon terminals in the neurohypophysis are supported by so-called pituicytes, which are characterized by the expression of the TTF-1 transcription factor (absent in classic GFAP-positive astrocytes) ()()(). These cells show elongated processes often running in parallel with axons and demonstrate only patchy GFAP and S100 expression.

The vessels of the hypophysis cerebri have been extensively described and reviewed ()()()(). The arteries of the hypophysis arise from the internal carotids via a single inferior and multiple superior hypophysial arteries. The arteries of the median eminence and infundibulum end in sprays of capillaries. In the median eminence, these form the external (mantle) plexus and the internal (deep) plexus that are both drained by the long portal vessels some of which terminate in the adenohypophysis. Short portal vessels run from the lower infundibulum to the pars anterior. Both types of portal vessel open into the vascular sinusoids lying between the secretory cords in the adenohypophysis, providing most of the blood; there is no direct arterial supply to this region ()(). The portal system is considered to carry hormone-secreting factors from the hypothalamus ()()(). Another notable feature of the rostral portion of the stalk are tortuous capillary loops surrounding a central capillary, termed gomitoli (). These structures are composed of a central muscular artery surrounded by a spiral of capillaries. Although their function is unknown, the complexity of these gomitoli suggests that they may regulate the rate of blood flow to the adenohypophysis thereby regulating the flow of trophic factors.

The venous drainage of the neurohypophysis is by three possible routes: to the adenohypophysis via the long and short portal vessels, via the large inferior hypophyseal veins into the dural venous sinuses or to the hypothalamus via capillaries passing to the median eminence. The venous drainage carries hypophysial hormones from the gland to their target tissues and also facilitates feedback of secretions. In contrast, the venous drainage of the adenohypophysis appears restricted. It is possible that flow in the short postal vessels could be reversed explaining the postulated “short feedback loop”. These models of hypophysial blood flow are of importance to the mechanism of hormone secretion. It is not certain whether the median eminence represents the final common pathway for neural control of the adenohypophysis or the entire neurohypophysis may be involved; its capillary bed may selectively determine the destination of both hypothalamic and pituitary secretions, conveying some to the glandular pituitary, others to distant target organs and yet others to the brain ().