Pituitary Anatomy and Development

Lechan, Ronald M.; Arkun, Knarik; Toni, Roberto

doi:10.1007/978-3-030-11836-5_2

Ronald M. Lechan⁴,
Knarik Arkun⁵ &
Roberto Toni^6,7,8,9

Part of the book series: Contemporary Endocrinology ((COE))

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3 Citations

Abstract

Although descriptions of the pituitary gland can be traced to the second century A.D., major advances continue to be made with respect to elucidating the organization and functional anatomy of this organ system. On the surface, the pituitary gland would appear to be a rather simple structure, containing two lobes (anterior and posterior) that are well visualized by MRI imaging, and gives rise to secreted hormones involved in the regulation of peripheral, target organs. However, the development, organization, and inner workings of the pituitary are vastly complicated. The anterior pituitary is comprised of three subdivisions including the pars distalis, pars intermedia, and pars tuberalis, all derived from Rathke’s pouch, but only the function of the pars distalis is well understood in man. Included among the complexity of pituitary anatomy is an expanding list of factors involved in the development of the anterior pituitary, a somewhat distinct topography for most the classic cell types in the pars distalis, morphological and physiological evidence for heterogeneity among these cells, evidence for cell clustering that may be involved in amplifying signals from the hypothalamus, local regulatory control mechanisms mediated by paracrine and autocrine secretion and modulation by glial-derived cell types, and the presence of stem cells that may be involved in postnatal plasticity of the anterior pituitary.

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Pituitary Gland Embryology, Anatomy and Physiology

Pituitary Gland

The Pituitary Gland: Functional Relationship with the Hypothalamus, Structure, and Physiology

Keywords

Historical Anatomy

The most ancient suggestion of a pituitary gland in man can be traced to the Tantra Yoga, elaborated by the pre-Aryan, Dravidic culture and Aryan Brahmanic, Ayurvedic medicine of fifteenth to fifth centuries B.C. [1]. Although Vedic medical doctrine prohibited dissection of human cadavers, it recognized an “energy center ” in the brain called ājñā chakra in ancient Sanskrit, believed to regulate consciousness and perception of “self.” This center was symbolized by two petals of the lotus flower, reminiscent of the two thalamic masses [2], and, possibly, the two lobes of the pituitary gland [1]. According to the Tantric anatomy, this region included numerous efferent channels (nerve fibers) called nadis [3], which we now recognize to contain the hypothalamic tuberoinfundibular system (for historical reviews, see [4,5,6,7]).

The first anatomical description of the pituitary gland on record, however, was during the second century A.D. by Galen of Pergamon. In Anatomicae Administrationes, he described a physical connection between the pituitary and infundibulum of the hypothalamic third ventricle and its association with a surrounding vascular network that he called “rete mirabilis. ” He proposed this unique, arterial structure had a key role in the regulation of body energy, sensation, and impulse, which he referred to as “vital and animal spirits.” Galen was influenced by the ancient, Greek anatomist, Herophilus of Alexandria (third century B.C.), however, to whom he credited the discovery of the rete mirabilis [4, 5, 8, 9]. Although absent in humans, the rete mirabilis is a well-developed structure in a number of animal species (Carnivora, Cetacea, Edentata, and Ungulata) and equivalent to the suprahypophysial, circuminfundibular, and prechiasmal arteriolar-capillary plexus of man [4,5,6]. In De Usu Partium, the major treatise of Galenic physiology, the pituitary gland is described as a receptacle for brain “waste” in the form of mucus or phlegm (pituita in Latin) that accumulates in the third ventricle as a result of the “metabolism” of “body energy” at the level of the rete mirabilis. This material was proposed to drain along the hypothalamic infundibulum and “filtered” by the pituitary gland before exiting through the nasal cavities [4, 5]. Although now archaic in concept, it is of interest that evidence for brain paravascular channels that drain into sinus-associated dural lymphatics and perivenular lymphatics (so-called glymphatic system) have recently been described [8], re-energizing the Galenic concept of nasopharyngeal extracerebral transport of “metabolic impurities” from the central nervous system.

Galenic concepts dominated for several centuries as indicated by drawings of the pituitary gland and rete mirabilis by Leonardo da Vinci in 1508 (Fig. 2.1a, b), but he also provided the first detailed drawings of the anatomy of the human skull base. These included transverse and sagittal views of the cranial fossa , giving a detailed anatomical depiction of the association between the third ventricle/pituitary stalk and the cranial vault, facial bones, and nasal/oral cavities (Fig. 2.1c–e). During the same period, Johannes de’ Ketam published the superficial cranial projection of somatesthesia (Fig. 2.1f) in Man of Diseases (1491) , corresponding to the frontal area where hyperalgesia occurs with stretching of the diaphragma sellae, as with a pituitary macroadenoma that extends into the suprasellar cistern [9]. In 1511, Michelangelo Buonarroti painted the fresco, Creation of Adam, on the ceiling of the Sistine Chapel, believed to be the first depiction of the hypothalamic-pituitary region (Fig. 2.1g, h) [4, 5].

It was not until the sixteenth century, however, that Berengario da Carpi in Isagoge Breves first challenged the Galenic concept of the pituitary gland as a basin that filtered cerebral waste products, based on his work with human cadavers, and described the sphenoid sinus as a route to the sella turcica [4, 5]. Shortly thereafter, Andreas Vesalius in Tabulae anatomicae sex (1538) described the venous drainage from the cranial vault, which recapitulates what we now recognize as the inferior and superior petrosal and sphenoparietal sinuses (Fig. 2.2a), and although demonstrated that the rete mirabilis originates from the internal carotid artery, surrounds the pituitary fossa, and then widens symmetrically and superiorly to vascularize the infundibulum and hypothalamic floor, he erroneously reported that it was present in man (Fig. 2.2b). Subsequently, in De Humani Corporis Fabrica (1543) , he detailed the anatomical relationships between the pituitary gland and the hypothalamic infundibulum, diaphragma sellae, internal carotid arteries, and oculomotor nerves and, although now denying the presence of the rete mirabilis in man, held fast to the Galenic dogma by describing bony ducts of the cranial base he believed to drain brain mucus (Fig. 2.2c–f). The contemporary of Vesalius, Gabriele Fallopius, similarly argued against the presence of the rete mirabilis in man, but it was not until the seventeenth century that Thomas Willis raised the possibility in Cerebri Anatome that “humors” from blood perfusing the ventral surface of the brain are carried to the pituitary gland, unwittingly anticipating current concepts of releasing and inhibiting factors for adenohypophysial regulation [4, 5]. The Galenic idea that the pituitary gland filters brain secretions into the nose was also criticized by Konrad Victor Schneider during the same period in Liber Primus De Catarrhis (1660) , showing that the cribriform plate of the ethmoid bone was impervious to drainage from the central nervous system, and by Willis’ assistant, Richard Lower, in his 1670 Tractatus de Corde , observing that the infundibular connection to the pituitary gland was filled with a gelatinous substance that would obstruct the possibility of mucous percolation from the third ventricle into the gland (see [6] for historical review).

Further advances were made in the eighteenth century by the French clinician and anatomist, Joseph Lieutaud, in Essais Anatomique (1742) , who introduced the term “pituitary stalk ” (la tige de la glande pituitaire) and described stalk vessels we now recognize as part of the portal circulation. In 1767, Luigi Galvani in Disquisitiones Anatomicae Circa Membranam Pituitariam showed that mucus passing through the nostrils originates from glands in the nasal mucosa and not the pituitary [10], and in 1791 Samuel Thomas von Sömmerring coined the term “hypophysis ” in Hirnlehre und Nervenlehre [5]. However, it was not until the late in the nineteenth century and throughout the twentieth century that a new renaissance in the understanding the anatomy and importance of the pituitary gland was begun, coincident with the development of new and powerful histochemical and molecular techniques, and continues into the present century. Included was work by Santiago Ramón y Cajal in 1894 using the Golgi’s silver impregnation technique to elucidate the connection between the hypothalamus and posterior pituitary (supraoptic-hypophysial tract), the discovery of hypothalamic neurosecretion by Ernst Scharrer in 1928, the finding by Popa and Fielding in 1930 of an interconnection between the pituitary and hypothalamus through the “hypophyseo-portal vessels” (although misinterpreted as blood flowing from the pituitary upward to the hypothalamus), evidence by Harris and Green between 1935 and 1955 that the blood flow in portal vessels was from the hypothalamic median eminence to the pars distalis of the pituitary gland and that electrical stimulation of the hypothalamus was ineffective in eliciting a pituitary response if the pituitary stalk was severed, and descriptions of the neurosecretory nature of the neurohypophysis by Wolfgang Bargmann in 1949 using the Gomori’s histochemical method [11] (see also [6] for historical review). Many advancements have been made since, and those relevant to the current understanding of the anatomy of the pituitary gland are alluded to in the following sections. A timeline of major, historical breakthroughs in elucidation of the functional anatomy of the mammalian pituitary gland is summarized in Table 2.1.

Table 2.1 Timeline of major, historical breakthroughs in elucidation of the functional anatomy of the mammalian pituitary gland

Full size table

Macroscopic Anatomy

Landmarks of the Sellar Region

The pituitary gland lies in the central part of the sella turcica (pituitary fossa), a saddle-shaped groove in the endocranial, superior surface of the sphenoid bone corresponding to the median part of the middle cranial fossa (Fig. 2.3a). On a lateral skull projection, the sella and pituitary lie 5–6 cm anterior to the point of the orthogonal intersection between Frankfurt horizontal plane and a vertical line descending from the vertex of the cranial vault (posterior to the bregma) to the center of the external acoustic meatus (Fig. 2.3b). Bordering the sella turcica is a bony thickening at the apex of its anterior wall, the tuberculum sellae, protruding upward as much as 3 mm to terminate into two, small, bony eminences, the middle clinoid process. Lateral and above are the anterior clinoid processes, forming the tip of the lesser wings of the sphenoid. The tuberculum sellae also forms the posterior wall of the chiasmatic groove into which rests the optic chiasm (Fig. 2.3a, c, d). Just above the optic chiasm are the anterior cerebral and anterior communicating arteries of the circle of Willis, the lamina terminalis, and third ventricle of the hypothalamus (Fig. 2.3d).

Lateral to the sella are the cavernous sinuses (Fig. 2.4a–c), a collection of spaces, loculated by fibrous septa between the outer periosteal and inner meningeal dural sheaths. The outer periosteal dural sheath covers the floor and anterior and posterior walls of the sella. The inner meningeal dura forms the lateral wall and roof of the cavernous sinus, gives rise to a very thin medial meningeal lining that serves as its medial wall and adheres to the capsule of the pituitary gland [12], and fuses with the cerebellar tentorium at the roof and superior aspects of the lateral walls of the sella turcica (Fig. 2.4c). Venous blood from the cavernous sinus (Fig. 2.4a) exits via endocranial tributaries of the internal jugular veins that include the superior and inferior petrosal sinuses and exocranial tributaries of the internal jugular vein, including the ophthalmic and facial veins.

Within the space between the medial and lateral walls of the cavernous sinus (Fig. 2.4a), a loose, reticular, connective tissue membrane envelops the oculomotor (III), trochlear (IV), abducens (VI), ophthalmic (V₁), and maxillary (V₂) branches of the trigeminal nerves and a sympathetic plexus that surrounds the internal carotid artery [12]. The internal carotid artery is separated from the pituitary gland by at least 2 mm but occasionally can indent the pituitary parenchyma. Once in the cavernous sinus, the internal carotid artery courses horizontally and anteriorly for ~2 cm (Fig. 2.4b–d), then forms a genu forward, and is fixed to either the anterior clinoid process by a dural ring (carotid collar) or between the anterior and middle clinoid processes by an osseous ring, the caroticoclinoidal ring.

Posteriorly, the sella turcica is bordered by the dorsum sellae (Fig. 2.3a) and the posterior clinoid processes (Fig. 2.3a). Anterior and caudal to the dorsum sellae, venous lacunae are found between the periosteal linings and the pituitary capsule [13], including the posterior intercavernous sinus and basilar sinus [14]. Connections between the posterior intercavernous sinus and the anterior intercavernous sinus (Fig. 2.4d), which run along the anterior wall of the sella, contribute to a ring of venous lacunae around the pituitary called the circular sinus . The basilar sinus collects blood from the superior and inferior petrosal sinuses and is the most consistent, intercavernous connection across the midline [14].

Superiorly, the inner meningeal layer forms the roof of the cavernous sinus (Fig. 2.4a) and expands medially to form the roof of the sella turcica (Fig. 2.4a, b), called the diaphragma sellae [15]. It is located ~5–10mm below the optic chiasm [16] and, in most instances, extends from the tuberculum sellae to the dorsum sellae measuring 11–13 × 8–10 mm (w × l) to cover the pituitary gland [17]. It has a central, circular opening of ~5 mm to allow the passage of the pituitary stalk (Fig. 2.4a, b). At the level of this orifice, the inner meningeal layer and leptomeninges (arachnoid and pia mater) of the suprasellar arachnoid cisternae (suprachiasmatic, interpeduncular, and lamina terminalis) and base of the brain fuse with the capsule of the pituitary gland [13], preventing the development of subdural and infra-arachnoid spaces within the pituitary fossa. However, in ~50% of normal subjects, an outpouching of arachnoid protrudes into the sella through the central opening and can give rise to an empty sella (see section “Radiologic Anatomy”) or, if resected, predispose to the development of a cerebrospinal leak following transsphenoidal surgery [18].

Inferiorly, the floor of the sella turcica is made up of a thin layer of the bone covered by outer periosteal dura, sometimes containing an inferior intercavernous sinus similar to that described above pertaining to the sinuses in the posterior and anterior sellar walls. The sellar floor separates the pituitary fossa from a pneumatic cavity within the body of the sphenoid bone, the sphenoid sinus. This sinus has an average depth of ~2 cm [14] and communicates with the nasal space (Fig. 2.5a) through an ostium that opens superiorly and behind the superior nasal conchae of the ethmoid, corresponding to the sphenoethmoidal recess (Fig. 2.5b). Rarely, the sellar floor connects the pituitary fossa with the posterior part of the nasopharynx through a craniopharyngeal canal, terminating ~1.5 mm behind the posterosuperior angle of the nasal vomer [19,20,21]. The craniopharyngeal canal, a remnant of the migration pathway taken by the embryonic pituitary to reach the sella turcica (see section “Embryologic Anatomy”) and lined by dura mater, may persist in the adults and contain functional pituitary tissue [19].

The sphenoid sinus serves as the primary, anatomical landmark for the transsphenoidal approach to the sella turcica. In ~75% of adults, the sphenoid sinus is entirely pneumatized and located below the floor of the sella turcica, even extending up to the clivus (sellar type) (Fig. 2.5a, b). Otherwise, it terminates at the level of the anterior sellar wall (presellar type) (Fig. 2.5c). In both instances, the sellar floor thickness ranges from 0.1 to 1.5 mm. In young children, however, a pneumatized sphenoid is lacking, and the floor of the sella can be up to 10 mm thick. Most often (~70% of adults), the sphenoid sinus is asymmetrically divided into two, separate spaces by a bony septum (intersphenoid septum) but can contain multiple smaller septa to further loculate each space [14]. The internal carotid artery courses along and external to the lateral walls of the sphenoid sinus, giving rise to a carotid prominence inside the sinus.

Craniometric parameters used to identify and/or predict changes in the macroscopic morphology of the pituitary gland include the sellar length and width. The sellar length is greatest in the anterior-posterior diameter of the pituitary fossa when measured at the level of the tuberculum sellae or below, whereas the sellar width is defined as the distance between the two carotid sulci at the level of the sellar floor (Fig. 2.3c). In most Caucasian adults, the upper limit of normal is 17 × 15 mm [14]. The depth of the sella generally does not exceed 13 mm when the greatest distance between the sellar floor and a perpendicular line connecting the tuberculum and dorsum is measured [14].

Pituitary Gland

The pituitary gland is composed of an anterior, epithelial lobe (anterior pituitary or adenohypophysis) and a posterior neural lobe (neurohypophysis) (Fig. 2.6a). In man, the wet weight of the entire gland is proportional to its volume. It increases from ~100 mg at birth to ~500–600mg during the second decade depending upon ethnicity [22, 23] and may even reach 800 mg in males and 900 mg in females [24]. Women generally have a pituitary that is ~20% larger than men [22] and can double its weight during pregnancy and with a progressive increase in multiparity [24]. These changes are confined to the anterior lobe, however, as the size and weight of the posterior lobe remain fairly constant throughout life [22, 25] and it does not display sexual dimorphism [26]. In general, the adult hypophysis measures approximately 10 mm in length, 10–15 mm in width, and 5 mm in height [22].

The entire gland is surrounded by a fibrous capsule organized into two layers (Fig. 2.6c). The first is an inner layer of lamina propria made up of collagen types 1–5 [27] that gives rise to fibrous trabeculae that penetrate the adenohypophysial parenchyma [13] and segments it into three, main territories, a central mucoid wedge (named because of its strong PAS positivity, otherwise known as the pars interloralis , see Figs. 2.15a, e and 2.17b) and two lateral wings [28]. These fibrous trabeculae (called the fibrous core ) provide passage for arterial branches that perfuse adenohypophysial parenchyma [29] and described further below. The second is a thicker, external layer made up of collagen types 1, 2, and 4 [13] that forms the lateral walls and roof of the sella [27, 30]. The external layer is a periphypophysial extension of the dural sheath and presumed to be the true pituitary capsule [13]. Since the capsule is loosely attached to the lamina propria through connective fibers that fills a potential space between them, the anterior lobe retains some degree of passive movement, as observed in cases of adenohypophysial displacement to one side of the sella in the presence of an enlarging pituitary adenoma [13]. In contrast, at the level of the neurohypophysis, the two adenohypophysial capsular layers fuse to each other, preventing movement of the posterior pituitary [13].

The anterior lobe contains three subdivisions including the pars distalis, pars intermedia, and pars tuberalis. The pars distalis lies adjacent to the pars nervosa but demarcated by an epithelial lamina corresponding to the pars intermedia. Rarely, the pars distalis envelops the pars nervosa or is detached from it, resulting in protrusion of the neurohypophysis into a depression of the dorsum sellae [24]. The pars distalis makes up the bulk of the anterior pituitary and contains all of the hormone-secreting cells of the adenohypophysis (see section “Microscopic Anatomy”). The pars intermedia lies between the pars distalis and the posterior pituitary, representing what remains of the posterior loop of Rathke’s pouch (see section “Embryologic Anatomy”). The pars tuberalis can be subdivided into a superior part attached to the hypothalamic median eminence, and an inferior part that surrounds the infundibular stem (Fig. 2.6b) but separated from it by a fibrovascular lamina (septum tuberalis) that contains the portal vessels [29, 31].

The neurohypophysis is comprised of the posterior pituitary and infundibular stem (the neural component of the pituitary stalk, the latter also including the pars tuberalis) that extends from the floor of the hypothalamus (a protrusion of the hypothalamic tuber cinereum that contains the infundibular recess of the third ventricle) to the posterior pituitary. Where the infundibular stem joins the posterior pituitary, the pars distalis forms two, symmetric groves called the loral groves, into which the loral arteries pass to enter the pars distalis (see section “Vascularization of the Pituitary Gland”). The lower part of the stem forms a genu that displaces adenohypophysial tissue anteriorly and is covered by a continuation of the septum tuberalis (described above) called the genual septum . It is through the genual septum that the portal vessels as well as other pituitary arteries pass into the pars distalis (see section “Vascularization of the Pituitary Gland”).

Pituitary tissue can also be present in the nasopharynx, commonly referred to as a pharyngeal pituitary [32]. This structure is a residual of Rathke’s pouch during its migration from the oral cavity to the middle cranial fossa (see section “Embryologic Anatomy”) and situated in the mucoperiosteum between the sphenoid and vomer bones [33]. Typically, it is observed as a compact, elongated cell group 2–5 × 0.2–0.5 mm (l × w) that contains an incomplete fibrous capsule and occupies a volume ranging from 0.13% to 0.5% of the normal pituitary [34, 35]. All cell types in the pars distalis are also present in the pharyngeal pituitary [34, 36], and because of its connections with the sellar hypophysis via transsphenoidal venous and arterial vessels originating from the vomerosphenoidal fossa, sellar intercavernous sinus, sellar arteries, and possibly stalk portal vessels [37, 38], it can be functional [39].

Vascularization of the Pituitary Gland

The human pituitary gland is a highly vascular structure that receives both direct (arterial) and indirect (sinusoidal) vascularization. Direct vascularization originates from the supracavernous portion of the internal carotid arteries that give rise to lateral and anterior superior hypophysial arteries and the intercavernous portion of the internal carotid artery that gives rise to the inferior hypophysial arteries. The lateral and anterior superior hypophysial arteries give off numerous short branches that course along the long axis of the infundibular stem and terminate in capillary complexes at its upper part. The superior hypophysial artery also gives rise to the loral artery (also known as the middle hypophysial artery or artery of the trabecula) [40, 41]. It enters the superior surface of the anterior lobe at the homolateral loral groove to perfuse the region between the mucoid wedge and the lateral wings of the pars distalis and gives off branches that extend upward onto the surface of the pars tuberalis to anastomose with long branches of the anterior superior hypophysial artery [40], contributing to the vascularization of the pituitary stalk and a small part of the posterior pituitary [29]. Collectively, therefore, the superior hypophysial artery serves both the stalk and anterior lobe [42].

The inferior hypophysial artery on either side of the pituitary divides into ascending and descending branches running in the groove between the anterior and posterior pituitary lobes and anastomoses with each other, giving rise to an arterial circle that penetrates the posterior lobe or courses along the capsular surface of the neurohypophysis (Fig. 2.6c) to perfuse this tissue [29, 40]. Some vessels also extend over the inferior surface of the pars distalis to penetrate adenohypophysial parenchyma [29]. Collectively, this arrangement indicates that the inferior hypophysial artery primarily serves the posterior lobe and, to a minor extent, the adenohypophysis [42].

The most critical source of the vascularization to the anterior pituitary, however, is the pituitary portal system, originally identified as “portal veins” because its vessels act as a link between the arterial blood of the hypophysial arteries and venous blood of the hypophysial veins [43]. However, technically, the human hypophysial-portal veins are really fenestrated sinusoids originating from the surface of the hypothalamic median eminence and infundibulum [29]. They remain superficial and collect a network of deeper sinusoidal capillaries stemming from the branches of the superior and inferior hypophysial arteries that form capillary tufts (so-called gomitoli) within the neural tissue of the hypothalamic infundibulum, infundibular stem, and neurohypophysial genu [29]. The portal sinusoids include a posterior and anterior group. The posterior group gives rise to the long portal vessels that enter the bulk of the pars distalis, whereas the anterior group is the source of the short portal vessels that form in a region of the infundibular stem beneath the pars tuberalis (septum tuberalis) (Fig. 2.6b) and neurohypophysial genu and terminate in the mucoid wedge and lateral wings of the pars distalis [29].

The venous drainage from the pituitary gland is primarily directed into the cavernous sinuses, although some venous blood also drains into the circular sinus and the inferior sinus. Portal sinusoids within the adenohypophysis join together to form small, collecting channels (the lateral and anteroinferior hypophysial veins) located lateral to the gland before emptying into one of its venous perihypophysial sinuses [40, 44]. Other veins are formed in the superior part of the pars distalis (superior hypophysial veins) and drain into a venous plexus at its dorsal surface. Ultimately, the pituitary blood drains from the cavernous sinuses into the superior and inferior petrosal sinuses. Some authors have also observed drainage from hypophysial stalk sinusoids into the sellar circular sinus [44] and the venous network of the pia mater [40], but this is only minor. Venous efferents from the posterior pituitary run parallel to the inferior hypophysial artery and mainly drain into the posterior hypophysial sinus and a plexus of veins lying posterior to the posterior pituitary (posterior venous network) that drain both the intercavernous/cavernous sinuses and cranial basilar sinus [44].

Embryologic Anatomy

In man, the anterior pituitary derives from a specialization of the embryonic ectoderm bordering the most anterior and ventral portion of the neural tube [45] that in the early, vertebrate embryo corresponds to the preplacodal ectoderm of the neural plate [46]. At the beginning of the 4th week of fetal development, the neural tube closes, but a cranial opening remains, the anterior neuropore, that quickly collapses to become the anterior wall of the proencephalic vesicle. Below the anterior neuropore is the frontotemporal ectoderm of the neural tube that adjoins with the mouth opening or stomodeum inferiorly. At the level of the most ventral and median part of the frontotemporal ectoderm, fusion occurs with ectodermal cells of the surface epithelium (the epidermis), enveloping the entire neural tube and body of the embryo [45]. This “mixed” ectodermal structure (neural tube ectoderm/surface ectoderm) invaginates backward into the stomodeum to line its roof but, at this stage, is not separated from the overlying neural tube by the mesoderm. Only later, the mesoderm interposes to form the sphenoid bone (see below), moving anteriorly from the notochord and terminating behind a temporary closure of the stomodeum, the fenestrated buccopharyngeal membrane. As a result, a “specialized” ectoderm develops anterior to the buccopharyngeal membrane, the adenohypophysial placode, the source of tissue lining the roof of the oral aperture. Whether in man, the adjacent neural crest forming the thickened “lips” of the anterior neuropore contributes to the adenohypophysial placode is not known. By analogy with other vertebrates, however, it is assumed that the preplacodal ectoderm is devoid of neural crest cells [46]. However, it is suggested that the adenohypophysial placode might contain neural crest cells [47], and recent immunocytochemical data in human embryos support this possibility [48, 49].

Around the 4th to 5th weeks of fetal development, the adenohypophysial placode emits a dorsally directed evagination, Rathke’s diverticulum, that moves upward throughout the mesoderm that is now interposed between the roof of the buccal cavity and the ventral surface of the proencephalon [50]. This mesoderm, called the prechordal ectomesenchyme (because it is positioned anterior to the notochord), contains neural crest cells arising from the mesencephalic crest [51]. Rathke’s diverticulum elongates inside the prechordal ectomesenchyme, forming a pharyngo-hypophysial stalk that will come in contact with the floor of the diencephalic vesicle which will become the hypothalamic infundibulum. At the same time, the future superior hypophysial artery develops from the ectomesenchyme below the diencephalic vesicle, giving off branches to the primordium of the hypothalamic infundibulum [52]. Around the 6th to 7th weeks of fetal development, the floor of the diencephalic vesicle extrudes a neural diverticulum, the primordium of the infundibular stem, that moves inferiorly toward the tip and posterior surface of Rathke’s diverticulum, the latter progressively closing to form a pouch or Rathke’s pouch that loses continuity with the oral cavity (Fig. 2.7a). At this stage, the placodal cells of the tip of Rathke’s pouch wrap around the primordial infundibular stem to eventually become the adenohypophysial pars tuberalis (see below) [50]. Rathke’s pouch separates from the stomodeal roof due to the development of cartilage of the primordial sphenoid bone (Fig. 2.7b). Only a mesenchyme-filled channel through the sphenoidal cartilage remains, the craniopharyngeal canal, that will later involute, although occasionally remains as a part of a developmental disorder [19]. During the 8th week of fetal development, sinusoidal connections with the superior hypophysial artery appear in the prechordal ectomesenchyme, invading Rathke’s pouch to become the intrapituitary fibrous septa and giving rise the primordial hypophysial-portal vessels that will later proliferate within the pars distalis [52]. During this developmental period, the prechordal ectomesenchyme also proliferates anteriorly and inferiorly to give rise to the so-called nasal trabecula (i.e., the primordium of the nasal septum) [53]. Thus, the cartilage of the nasal septum contains neural crest cells and of the same type believed to contribute to the development of the human pituitary [48, 49].

The ectomesenchymal area of the nasopharynx , at the interphase between the inferior surface of the developing sphenoid and the vomer bones, encases the posterior aspect of the nasal septum where the buccopharyngeal membrane ceases and Rathke’s pouch arises in the oral cavity. At this location, between the 8th and 10th weeks of fetal development, an ectodermal pituitary outgrowth, the bucco-hypophysial stalk, segregates between the external layer of ectomesenchyme (later forming the periosteum of the sphenoid) and the epithelial lining of the pharynx to become the pharyngeal pituitary. By the end of the first trimester of pregnancy, the pharyngeal pituitary is highly vascularized by branches of pharyngeal arteries and by venous conduits originating from intracranial venous sinuses in the region of the future sella turcica and exhibits signs of eosinophilic and basophilic histodifferentiation. However, numerous cells display cytological features of undifferentiated elements [54,55,56].

The prechordal ectomesenchyme of the sphenoid bone is also believed to be critical for the specification of different adenohypophysial cell types from placodal cells. Between the 8th and 9th weeks of fetal development, Rathke’s pouch forms three diverticula, a single median, and two laterals. The upper part of the lateral diverticula gives rise to the pars tuberalis, whereas the median diverticulum provides the epithelial bulk of the mucoid wedge in the fully differentiated gland. Simultaneously, the first corticotrophs and thyrotrophs differentiate in the lower diverticular parts in direct contact with the surrounding ectomesenchyme [50]. During the 13th week of fetal development, somatotrophs and gonadotrophs differentiate in the lower portions of the lateral diverticulum of Rathke’s pouch, increasing in number throughout the 21st–29th weeks. At these developmental stages, the neural lobe acquires a well-defined morphology (Fig. 2.7c), and the bulk of the corticotrophs differentiate in the walls of the median diverticulum, including that in contact with the primordial infundibular stem, the pars intermedia. Concurrently, thyrotrophs and gonadotrophs become detectable in the pars tuberalis. Since anencephalic fetuses lack corticotrophs and gonadotrophs, it has been suggested that early contact with the primordial neurohypophysial tissue may have a key role for the histodifferentiation of these two pituitary cell types in man [57]. Finally, starting in the 21st week of fetal development, lactotrophs are identified throughout the primordial pars distalis (Fig. 2.7d) that includes all three diverticula of Rathke’s pouch [50].

During the last trimester, pituitary tissue completely surrounds the infundibular stem, and the primordial pars distalis enlarges laterally to give rise to the lateral wings, as in the adult (Fig. 2.7c). Although the cavity of Rathke’s pouch is still present, follicular structures are progressively formed in its vicinity as a part of protrusions from its walls, the posterior one becoming the pars intermedia. Due to the strong morphological similarity between folliculostellate cells and the free surface epithelium of Rathke’s cavity, it is presumed that the cells that make up the follicular structures are precursors of the human folliculostellate cells [50]. Numerous genes and transcription factors are involved in regulating the various developmental steps of the human pituitary and are extensively reviewed elsewhere [58,59,60,61,62,63]. A summary of transcription factors relevant to human, pituitary morphogenesis, and histodifferentiation is provided in Table 2.2, based on clinical outcomes when any of these factors are mutated. A schematic summary of the sequential actions of transcription and other morphogenetic factors to induce the different adenohypophysial cell types is shown in Fig. 2.8.

Table 2.2 Transcription factors associated with genetic causes for human disorders of pituitary development and secretion

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Radiologic Anatomy

The introduction of computed tomography (CT) and magnetic resonance imaging (MRI) into medical practice has provided highly sensitive tools to elucidate the normal anatomy of the pituitary gland and to identify pathology. In particular, by MRI, the anterior and posterior pituitary are well delineated in T1-weighted images by the so-called bright spot of the posterior pituitary (Fig. 2.9a), the posterior pituitary being hyperintense relative to gray matter despite the absence of contrast [64]. The bright spot is observed in up to 100% of normal adults, although can be absent in older individuals, possibly due to reduced storage of neurosecretory material. Typically, the bright spot measures between 1.2 and 8.5 mm in its greatest diameter and between 0.4 and 4.4 mm in the axis perpendicular to the longest axis [64]. Anything larger should raise suspicion of the underlying pathology such as a Rathke’s cleft cyst (Fig. 2.9b) or hemorrhagic pituitary adenoma. It has been proposed that the bright spot can be a useful diagnostic tool to differentiate central diabetes insipidus from psychogenic polydipsia, as in central diabetes insipidus, the bright spot is absent [65] (Fig. 2.9c), whereas in psychogenic polydipsia, the bright spot is present, perhaps even larger than normal due to increased accumulation of neurosecretory material [66, 67]. The posterior pituitary has tremendous regenerative capacity such that with transection of the pituitary stalk, a new, functional posterior pituitary can form, apparent as a bright spot in an ectopic location, generally the suprasellar cistern (Fig. 2.9d).

The anterior pituitary is isointense to gray matter on T1-weighted images and isointense to hypointense on T2-weighted images and generally has a flat or concave superior surface (Fig. 2.9a). In keeping with the macroscopic anatomy (see above), the pituitary volume by MRI shows significant differences between the sexes and with aging [68,69,70,71]. In general, the anterior pituitary is small and flattened during most of childhood but enlarges during puberty, somewhat more in girls than boys, and then decreases in size in the aged [72,73,74]. In a Croatian study of 199 adults (91 males and 108 females), the mean pituitary volume by MRI in young men (ages 20–29) was 539.2 mm³ and in females 680 mm³, whereas in the aged (ages 70–79), it was 450.4 mm³ in males and 636.3 mm³ in females [68]. Adolescent women may have a convex superior border to the pituitary gland suggesting anterior pituitary hyperplasia (Fig. 2.10a), but this can be a normal appearance. A similar enlargement of the anterior pituitary by MRI is characteristic of pregnancy due to the proliferation of lactotrophs [75, 76], increasing in volume by as much as 120% by the third trimester, and may extend into the suprasellar cistern. This phenomenon reflects the tremendous plasticity intrinsic to the function of the anterior pituitary, capable of responding to a changing hormonal milieu. Marked enlargement of the anterior pituitary can also be observed in severely hypothyroid individuals due to hyperplasia of anterior pituitary thyrotrophs and in Addison’s disease due to corticotroph hyperplasia, fully reversible with replacement of the deficient hormones [77, 78]. Anterior pituitary volume has also been observed to increase in association with anxiety and depression [79], likely secondary to the activation of the hypothalamic-pituitary-adrenal axis.

Occasionally, the anterior pituitary can appear flattened to the base of the sella turcica, commonly described as an “empty sella ” (Fig. 2.10b). While this appearance can be indicative of underlying pathology (e.g., a pituitary adenoma that has undergone apoplexy, end stages of anterior pituitary hypophysitis, intracranial hypertension) [80], it may also be a normal variant due to herniation of arachnoid and cerebrospinal fluid into the sella turcica through an incompetent diaphragma sellae (see above, Pituitary Anatomy). Small cystic structures less than 2–3 mm can be observed on occasion in the central portions of the pituitary due to remnants of Rathke’s pouch but incidental findings and of no real clinical significance.

The pituitary stalk is well visualized on MRI as a midline structure arising from the base of the hypothalamus coursing through the suprasellar cistern to terminate in the posterior pituitary (Fig. 2.9a). The characteristic tapering of the stalk from superior to inferior is due to the infundibular recess of the hypothalamus that results in an invagination of cerebrospinal fluid into the proximal portion of the stalk as an extension of the third ventricle. Using high-resolution MRI (3T MR) in 29 healthy volunteers ages 21–43, the stalk diameter at the level of the optic chiasm measured 3.25 ± 0.39 mm, whereas at the pituitary insertion, it was 2.32 ± 0.39 mm [81]. On T2-weighted images in the majority of normal subjects, the central portion of the stalk is hyperintense compared to cerebral white matter due to neurosecretory material en route to the posterior pituitary and surrounded by a peripheral rim of isointensity, thought to represent pars tuberalis. Although stalk deviation often suggests underlying pathology, minor deviation of the stalk can be seen normally, particularly if there is some sloping of the sellar floor due to an eccentric location of the intersphenoid septum [82] (Fig. 2.10c).

The vascular anatomy of the pituitary, namely, that the posterior pituitary receives an arterial supply and the anterior pituitary is primarily (although not exclusively, see above, Vascular Anatomy) fed by sinusoidal blood coming from the portal circulation, can be appreciated with dynamic imaging of the pituitary in which MRI sequences are captured simultaneously with the intravenous administration of gadolinium. As would be anticipated, initial sequences show enhancement of the posterior pituitary and base of the hypothalamus, followed by enhancement of the pituitary stalk and finally the anterior pituitary (Fig. 2.11a–c) [83].

Many of the landmarks around the pituitary gland described above can also be well visualized by MRI, including the optic chiasm and structures in the cavernous sinus. The optic chiasm lies above the pituitary gland and can be central (directly over the pituitary ~65% of cases as shown in Fig. 2.9a), prefixed (more anterior to the pituitary ~25%), or post-fixed (more posterior over the pituitary ~10%). It is separated from the pituitary by the suprasellar cistern, which appears as a pentagonal, cerebrospinal fluid-filled space on coronal images (Fig. 2.12). The cavernous sinuses are located immediately lateral to the pituitary gland and contain vascular and neuronal elements. Most prominent in the cavernous sinus is the internal carotid artery, which appears hypointense on T1-weighted images because of the blood flowing through it (Fig. 2.12a). Cranial nerves III, IV, V₁, and V₂ sometimes can be visualized as hypointense filling defects by MRI, particularly cranial nerve III as shown in Fig. 2.12a. Sympathetic fibers encircle the carotid arteries but are not well visualized.

MRI has largely replaced CT as the imaging modality of choice to assess the pituitary gland, but the bony architecture of the sella turcica is best seen by CT (Fig. 2.13). The clivus is also well seen as it slopes posteriorly and inferiorly from the dorsum sellae, as is the sphenoid sinus (Fig. 2.13). Mean length and height of the sella turcica by CT tend to be greater in females than in males [84], reflecting that the female gland is larger than the male gland.

Imaging using positron emission tomography (PET) is gaining increasing utility as newer tracers are being developed. ⁶⁸Ga-DOTATATE , which binds to somatostatin receptors 2 and 5, shows reasonably good uniform uptake throughout the normal, anterior pituitary due to its high expression of somatostatin receptors [85]. In contrast, 18F-FDG PET shows preferential uptake into pituitary adenomas as well as other inflammatory and infiltrative disorders and little or no uptake into normal pituitary tissue [85], making it feasible to use PET imaging as a tool to identify tiny, functional pituitary adenomas by subtractive analysis.

Microscopic and Functional Anatomy

Anterior Pituitary (Adenohypophysis)

As noted above, the anterior pituitary is made up of three components, the pars distalis, the largest component of the anterior pituitary; pars intermedia, which is vestigial in man; and the pars tuberalis. It is the pars distalis, however, that is the main source of anterior pituitary hormone secretion.

Pars Distalis

The pars distalis is composed of nests or cords of large, epithelial, polygonal cells organized near venous sinusoids lined with a fenestrated epithelium into which secretory products from the anterior pituitary are collected. The nesting pattern is apparent in reticulin preparations that show a delicate, continuous border around acini (Fig. 2.14a), differentiating normal anterior pituitary tissue from adenomatous tissue that have a disrupted reticulin pattern (Fig. 2.14b). The cells of the normal pars distalis contain abundant cytoplasm that stain varyingly. Three cells types, acidophils, basophils, and chromophobes, were classically recognized using standard histological preparations such as hematoxylin and eosin (H&E) in which acidophils are red, basophils purple, and chromophobes light blue and PAS in which basophils are bright purple (Fig. 2.14c, d). A number of other stains have also been used in an attempt to identify specific cell subtypes, as illustrated in Fig. 2.14e, f, such as aldehyde thionine with PAS and orange G and Herlant stain. However, immunocytochemistry, which is now widely used in surgical pathology, best differentiates the five, major, cell types and six, secretory products of the anterior pituitary gland: somatotrophs (growth hormone), lactotrophs (prolactin), corticotrophs (adrenocorticotropic hormone), thyrotrophs (thyroid-stimulating hormone), and gonadotrophs (luteinizing hormone and follicle-stimulating hormone) (Table 2.3). The somatotrophs make up the acidophils (although lactotrophs can also be acidophilic), corticotrophs the basophils (although thyrotrophs can also be basophilic), and gonadotrophs, lactotrophs, and thyrotrophs the chromophobes. In fish, pituitary cell types tend to be highly organized into distinct zones, with lactotrophs more rostral and somatotrophs more caudal in the pars distalis [86]. A topography is also retained in man (Fig. 2.15) with a tendency for somatotrophs to occupy more lateral regions of the pars distalis, lactotrophs the posterolateral region, and corticotrophs and thyrotrophs the anteromedial region or mucoid wedge, whereas gonadotrophs are widely dispersed [87]. Each of these cell types is regulated by hypothalamic releasing and inhibitory hormones after they are released into the portal vasculature for conveyance to pars distalis cells (see Lechan and Toni [5] for review).

Table 2.3 Classic cell types and secretory products of the anterior pituitary

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Corticotrophs are medium-sized cells and contain large, clear, cytoplasmic vacuoles known as “enigmatic bodies ” that are lysosomal complexes, easily identified on routine H&E sections. By electron microscopy, numerous secretory granules can be seen along with bundles of intermediate keratin filaments. ACTH immunostaining decorates the cytoplasm of corticotrophs by immunostaining secretory granules, but not keratin filaments or lysosomal bodies [88]. In response to excess glucocorticoids, an accumulation of intermediate filaments results in Crooke’s hyaline change in corticotrophs, a pale, pink, glassy, ringlike staining of the cytoplasm on H&E. These changes are readily identified by immunostaining for low-molecular-weight keratins such as CAM5.2 and by demonstrating displacement secretory granules to the cell membrane edges with ACTH antiserum [89]. In cases of extensive Crooke’s hyaline change, the keratin filaments will occupy almost the entire cytoplasm, the cells become larger, and the nuclei develop prominent nucleoli.

Somatotrophs comprise the largest cell population of the pars distalis and are round to oval shaped with round nuclei. Immunostaining with GH-directed antibodies shows particularly strong cytoplasmic immunopositivity and the best way to recognize these cells. By electron microscopy, active cells have prominent, lamellar, rough endoplasmic reticulum and large Golgi regions. The entire cytoplasm is filled with dense secretory granules measuring from 150 to 800 nm in diameter, and there is a prominent endoplasmic reticulum that changes with the activity of the cell [90].

Lactotrophs are also well delineated by prolactin antiserum. Ultrastructural morphology identifies cells with both dense and sparse granules, although sparsely granulated cells make up the majority of prolactin-producing cells that actively secrete the hormone. The endoplasmic reticulum is well developed with parallel arrays that can occasionally form concentric structures called the Nebenkern formation . Long cytoplasmic processes can project into the center of acini and wrap around gonadotrophs, providing morphologic evidence suggesting paracrine regulation (see below).

Mammosomatotrophs resemble somatotrophs but produce both growth hormone and prolactin, detected within the same cell by immunohistochemistry and even within the same secretory granule. Two types of mammosomatotrophs have been identified by electron microscopy including cells containing numerous, small electrodense granules (150–400 nm), and cells with large cigar-shaped granules ranging up to 2000 nm with variable density [91].

Thyrotrophs are medium- sized, angulated cells that contain an eccentric nucleus. The cells are filled with small secretory granules that measure 100–200 nm, short rough endoplasmic reticulum and large Golgi complexes.

Gonadotrophs can be bihormonal or contain only one of the gonadotropins. By electron microscopy, round Golgi complexes and numerous granules are characteristic. The size of secretory granules varies in males and females: smaller secretory granules in male and larger secretory granules in females. Gonadotrophs frequently show oncocytic change and squamous metaplasia in older individuals.

Several of the major anterior pituitary cell types can also be detected in the adult pituitary with antiserum directed against transcription factors involved in their embryologic development. Included are TPIT that can be detected in corticotrophs [92], Pit-1 that can be found in somatotrophs, lactotrophs and thyrotrophs [93], steroidogenic factor 1 (SF-1) that is present in gonadotrophs, and GATA-2 in gonadotrophs and thyrotrophs [94]. These transcription factors can be retained in pituitary adenomas, facilitating the identification of their cell type [95]. All anterior pituitary cell types also can be identified with antiserum to the epithelial marker, CAM5.2 (low molecular weight keratin), and to the neuroendocrine marker, synaptophysin. Immunocytochemistry for alpha subunit also identifies cells producing LH, FSH, and TSH, since all are glycoprotein hormones and contain a common alpha subunit.

There are also small populations of other cellular subtypes in the pars distalis. Included are oncocytes that contain abundant mitochondria making the cytoplasm appear eosinophilic and granular by routine H&E stain and become more prominent with aging; null cells that are scattered throughout the pars distalis and, thereby, cannot be classified by hormone production and represent resting or stem cells; and follicular cells that tend to be seen in areas of cell injury or adjacent to tumors, formed from somatotrophs, lactotrophs, and/or corticotrophs that surround damaged cells and become degranulated and dedifferentiated. The folliculostellate cell comprises approximately 5–10% of the pars distalis cell population and is described more fully below.

It is becoming increasingly recognized that the organization of the pars distalis is vastly more complicated than described above. First, there is morphological and physiological evidence for heterogeneity among the classical anterior pituitary cell types including at least three subtypes of somatotrophs (sparsely granulated cell, densely granulated cells, and, as described above, mammosomatotrophs) and functionally different lactotrophs [96,97,98]. Plurihormonal cells in the human pituitary are also commonly found, particularly for somatotrophs and lactotrophs in which up to 25% of somatotrophs and 15% of lactotrophs co-express FSH [87]. Up to 4% of thyrotrophs co-express FSH, ACTH, or LH [87].

Cell clustering has also been observed for several of the hormonal cell types in the pars distalis and to form networks that can extend distances over the pars distalis [99], presumably as a way to integrate or amplify signals from the hypothalamus. The organization of these networks tends to change with specific phases of development or alterations in physiologic milieu [99, 100], indicative of the plasticity of the pars distalis. For example, during lactation, there is proliferation and reorganization of lactotrophs into a honeycomb-like structure with increased contacts between the cells as a way to coordinate increased output of prolactin [99, 101]. Somatotrophs tend to form clusters that are interconnected by strands of single somatotrophs but become particularly prominent during puberty in association with the growth spurt [100].

In addition to the above, there is strong evidence that the microenvironment of hormonal-secreting cells in the pars distalis is an important component for cell regulation in conjunction with neurosecretion from the hypothalamus. This local, regulatory control mechanism is mediated by paracrine and autocrine secretion of pars distalis hormones utilizing an expanding list of peptides, growth factors, cytokines, binding proteins, gases, and neurotransmitters listed in Table 2.4 (see Denef for extensive review [102]). That some gonadotrophs are closely apposed to lactotrophs was first recognized by Nakane [103] and later demonstrated by Denef and Andries [104] that gonadotrophs secrete substances in response to GnRH that stimulate prolactin secretion. Namely, medium from a highly enriched population of gonadotrophs in culture treated with GnRH, when added to a highly enriched population of lactotrophs, induces prolactin secretion [105]. Candidate substances derived from gonadotrophs abound and include pituitary glycoprotein hormone alpha subunit (αGSU), a N-terminal fragment of POMC (POMC 1–74), neurotensin, angiotensin II, PACAP, calcitonin, and CART among a number of other substances [102]. Gonadotrophs may also modulate the secretion from somatotrophs and corticotrophs through paracrine interactions [102]. Autocrine regulation has been recognized for somatotrophs, which express growth hormone receptors [106] that when activated, exert an inhibitory action on its own secretion [106]. Other substances may also contribute to autocrine regulation of somatotrophs including ghrelin, TRH, leptin, enkephalin, NPY, and substance P [102]. Numerous other examples of autocrine control can be found in the literature including evidence that lactotrophs are under autocrine regulation by galanin, VIP may mediate the proliferative response of lactotrophs to estrogen, neuromedin B produced by thyrotrophs exerts an inhibitory effect on TSH secretion, and activin B produced by gonadotrophs selectively induces LH secretion without having an effect on FSH secretion [102].

Table 2.4 Nonclassical anterior pituitary substances and cell(s) of origin

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Paracrine regulation and network functioning are also facilitated by a nonhormonal cell type, the folliculostellate cell. The folliculostellate cell is a small, chromophobic, stellate-shaped cell with long, delicate cytoplasmic processes (Fig. 2.16) creating a meshwork in which the glandular cells of the pars distalis reside [107]. Because they are immunopositive for glial fibrillary acidic protein (GFAP), cytokeratin, vimentin, and fibronectin, they are believed to be of glial origin. Folliculostellate cells are also strongly immunopositive for S-100. These cells function as part of an intrapituitary regulatory center, modulating glandular cells of the pars distalis as an excitable network capable of transmitting signals over long distances by electronic coupling to each other through gap junctions and intercellular junctions (zona adherens) [102, 108]. Folliculostellate cells also make contact with hormonal cells in the pars distalis and, through the release of a variety of substances including cytokines and growth factors listed in Table 2.4, can modify pituitary hormone secretion [100, 102]. Among many examples include a paracrine action of folliculostellate cell-derived IL-6 in response to endotoxin contributing to the increase in ACTH from corticotrophs [109], basic fibroblast growth factor and glial cell-derived neurotrophic factor as permissive for the mitogenic effect of estradiol on lactotrophs [110] and regulation of lactotroph apoptosis [111], respectively, and a role in the luteinizing hormone surge [112]. Folliculostellate cells also contribute to organization of the extracellular matrix surrounding clusters of pars distalis cells by regulating collagen synthesis from pericytes through the release of TGFβ2 [113] and laminin from gonadotrophs [114] and potentially contribute to the stem cell population [115].

Pars Intermedia

The pars intermedia is located between the pars distalis and posterior pituitary, but there is no clearly defined boarder. Although well developed during fetal development in man, it involutes shortly after birth and in the adult consists of clusters of basophil cells (corticotrophs) around colloid-filled cysts in dorsal portions of the mucoid wedge and PAS positive (Figs. 2.15a and 2.17a), but in some cases only scant connective tissue can be found [116]. Here, corticotrophs tend to be smaller than in the pars distalis, have more granules, and are less sensitive to glucocorticoids as they do not develop Crooke’s hyaline change and contain fewer keratin filaments. Some of these cells comprise the basophil invasion and extend well into the posterior pituitary (Fig. 2.17b, c), found in approximately 62% of human autopsy series [117]. However, the basophil invasion is more often seen in aging men, although the significance of this phenomenon is unknown and there are no endocrine abnormalities recognized. The pars intermedia is primarily comprised of a single cell type that synthesizes pro-opiomelanocortin (POMC), but as opposed to anterior pituitary corticotrophs, these cells do not generally produce ACTH due to extensive processing of the prohormone [118]. Rather, the major peptide contained in pars intermedia cells is α-MSH, and hence, they are commonly referred to as melanotrophs . Extensive processing also results in the production of β-endorphin, but because it is N-acetylated, it does not have opiate activity [118]. Small clusters of ACTH-producing cells have also been identified in the vicinity of the pars intermedia but could also belong to the pars distalis.

As opposed to the pars distalis, the pars intermedia is essentially hypovascular [119, 120], although there is evidence that any secretory products from these cells can reach the peripheral bloodstream via the posterior pituitary vasculature [121]. However, the pars intermedia is directly innervated by axonal fibers originating from the hypothalamus. Included are dopamine- and serotonin-containing axons [122,123,124] and TRH-containing axons [125]. Melanotrophs also express dopamine D2 receptors [126] and TRH receptors [125]. The propensity for the pars intermedia to selectively recruit a neuronal innervation may relate to the ability of these cells to express brain-derived neurotrophic factor [127, 128]. While the physiologic significance of this innervation in amphibians is clear, as dopamine inhibits and TRH stimulates the release of α-MSH, allowing α-MSH to regulate pigment dispersion in dermal melanophores [129], the role of the pars intermedia in man is of uncertain physiologic importance. Nevertheless, the common occurrence of the basophil invasion in the posterior pituitary and evidence that these cells also produce α-MSH and have a high proliferative index indicative of active mitosis [117] suggest a potential, functional role for these cells in the adult human brain.

Marginal Zone

Although not considered one of the major subdivisions of the anterior pituitary, the region that comprises the first row of cells from each of the pars distalis and the intermediate lobe is referred to as the marginal zone and is conserved in the human pituitary [130]. The main cell population consists of ciliated epithelial cells that are attached to each other and co-express a variety of stem cell markers such as Sox2, Sox9, Gfra2, RET, Oct 4, SEA4, Prop1, and KLf4 [131]. Tracing experiments indicate that these cells are capable of migrating into the pars distalis and differentiating into mature, hormone-producing cells [132] and may underlie the plasticity of the anterior pituitary in response to physiological changes as discussed previously.

Pars Tuberalis

The pars tuberalis is composed of columns of cells separated by sinuses, very much like the structure of the pars distalis, but encircling the infundibular stem (Fig. 2.6b) and in close contact with the base of the median eminence superiorly and pars distalis inferiorly. The physiological role of the pars tuberalis in man remains somewhat enigmatic, but it is clear that it is part of the photosensing pathway in the CNS and, in some mammals and birds, has an established role in the regulation of seasonal reproduction, sexual behavior, and hibernation (for reviews see Wood and Loudon [133], Korf [134], Azzali et al. [135]). The majority of cells that make up the pars tuberalis (PT-specific cells) are immunoreactive for the common, glycoprotein alpha subunit (CGA) due to the presence of gonadotrophs and thyrotropes [136]. As opposed to thyrotrophs in the pars distalis, however, pars tuberalis thyrotrophs are smaller and lack receptors for TRH [137]. Rather, they express the melatonin MT1 receptor [138, 139], which, in response to melatonin, results in the expression and release of TSH as part of a complex, so-called retrograde pathway that by increasing type 2 deiodinase activity in third ventricular tanycytes, ultimately leads to the regulation of GnRH secretion in the mediobasal hypothalamus [140, 141]. Melatonin also appears to have an important role in the regulation of clock genes in the pars tuberalis including Clock, Bmal1, Per2, Cry1, and Cry2 [142] that serve to mediate the photoperiodic signal generated by melatonin. Evidence that the pars tuberalis can activate Iκ-Bα in response to endotoxin, indicative of cytokine signaling through the NF-κB pathway, also suggests a role in immune modulation and hypothesized contribute to the mechanism of nonthyroidal illness during infection [143].

The pars tuberalis may also be involved in the seasonal release of prolactin secretion from the pars distalis through an “anterograde pathway” utilizing a variety of other substances including neurokinin A, substance P, and endocannabinoids [134]. In man, the CB1 receptor is most highly expressed in folliculostellate cells and corticotrophs in the pars distalis, however, indicating that any effect of the pars tuberalis on prolactin secretion must be indirect through paracrine regulation in the pars distalis [136]. Given the high expression of CB1 receptors on corticotrophs, the release of endocannabinoids by the pars tuberalis may also contribute to the regulation of the hypothalamic-pituitary-adrenal axis through direct, inhibitory effects in the pars distalis [144, 145].

Posterior Pituitary

The posterior pituitary is the lowest part of a continuous bundle of nerve fibers that extend from the hypothalamic magnocellular neurons that produce vasopressin and oxytocin, pass through the internal layer of the median eminence that forms the base of the hypothalamic infundibulum, and then proceed into the infundibular stem to terminate in the posterior pituitary (see above, Pituitary Anatomy). This bundle is composed of numerous unmyelinated and sparsely myelinated axons and axon terminals containing large neurosecretory vesicles, specialized glial cells called pituicytes, and a rich capillary network (Fig. 2.17c, d). The neurosecretory material is largely made up of the nonapeptides, vasopressin and oxytocin, and their carrier proteins, derived from magnocellular neurons in the hypothalamic paraventricular and supraoptic nuclei, but a variety of other substances are also found in the posterior pituitary, co-contained in vasopressin and oxytocin terminals. Coexisting in vasopressin axon terminals are dynorphin, galanin, pituitary adenylate pituitary cyclase-activating polypeptide (PACAP), secretin, and glutamate and in oxytocin axon terminals, dynorphin and proenkephalin A-derived μ-opioid peptides (see Brown [146] for review). In addition, neurons synthesizing dopamine and norepinephrine originating from the hypothalamus and brainstem, respectively, also innervate the posterior pituitary [147].

The importance of vasopressin as an antidiuretic hormone and oxytocin in uterine contraction and milk letdown is well known. Coexisting substances in vasopressin and oxytocin neurons are presumed to modulate the secretion of vasopressin and oxytocin from the posterior pituitary and/or their dendritic processes in the hypothalamus [146]. This concept is supported by an inhibitory effect of dynorphin on phasic activity of vasopressin secretion [146] and the existence of kappa opioid receptors, the endogenous ligand for dynorphin, on nerve terminals in the posterior pituitary [148]. However, it is also possible that some substances, such as dopamine, are destined for regulation of the anterior pituitary by way of the short portal vessels [149] that interconnect the capillary beds in the posterior pituitary with the anterior pituitary [150].

Pituicytes comprise approximately 25% of the posterior pituitary and have been classified into parenchymatous and fiber subtypes [151]. Parenchymatous pituicytes are large cells and immunostain with thyroid transcription factor −1 (TTF-1), glial fibrillary acid protein (GFAP), and S100, whereas fibrous pituicytes, the most abundant pituicyte, are small cells and immunostain only with S100 (Fig. 2.17d). The significance of this morphologic distinction is uncertain. However, pituicytes contain processes that interconnect with each other through tight, gap, intermediate, and complex junctions, terminate on blood vessels, and envelop axon terminals containing vasopressin and oxytocin, indicative of an important role in regulating vasopressin and oxytocin secretion [152]. Namely, under basal conditions, pituicytes completely engulf the neurosecretory axon endings and interject their processes between secretory nerve endings and the basal lamina of the fenestrated vasculature. Dehydration, however, results in retraction of pituicyte processes (stellation) from axon terminals and at the vascular surface, favoring increased hormone release into the peripheral bloodstream. Pituicytes are also believed to be osmotic sensors and produce humoral factors such as galanin-like peptide (GALP) in response to hypertonic saline [153], which may contribute to the release of vasopressin and oxytocin from neuronal endings in the posterior pituitary [154]. Conversely, pituicytes release taurine in response to hypotonic conditions, inhibiting hormone release from the posterior pituitary [155]. Thus, as summarized by Rosso and Mienville [156], pituicytes may control neurohormone output by at least two major mechanisms, through structural modifications and by the release of hormone modulators.

Concluding Remarks

The pituitary gland comprises only a tiny fraction of the intracranial volume, yet as apparent from current understanding of its embryologic development, macroscopic and microscopic anatomy, and functionality, it is a highly complicated structure. Particularly exciting is the potential for regeneration of the pars distalis, given evidence for embryonic stem cells in the marginal zone of the pars intermedia and the remarkable plasticity of the adenohypophysis as apparent during adolescent development in women and in association with primary hypothyroidism, pregnancy, and primary hypoadrenalism. Evidence for communication between tanycytes in the hypothalamus and hormonal-producing cells in the pars tuberalis has provided new insights about the functionality of this portion of the anterior pituitary in animal models, but although also a well-established structure in man, its role is still unknown. While the pituitary has fascinated scientists over the centuries and a vast amount of knowledge has been amassed since the original Galenic concepts, we still have much to learn.

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Acknowledgements

We wish to thank Fulvio Barbaro, Elia Consolini, Marco Alfieri, and Davide Dallatana, Section of Human Anatomy and Museum BIOMED, University of Parma Parma, Italy, for invaluable help in preparing and photographing the anatomical material on the skull, cranial base, and microvascular anatomy of the human pituitary gland, and Dr. Arthur Tischler, Professor of Pathology, Tufts Medical Center, for his assistance with the histochemical preparations of the anterior pituitary.

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Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA
Ronald M. Lechan
Department of Anatomic and Clinical Pathology, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA
Knarik Arkun
Department of Medicine and Surgery, Unit of Biomedical, Biotechnological, and Translational Sciences, Section of Human Anatomy, RE.MO.BIO.S. Lab, Parma, Italy
Roberto Toni
Center for Sport and Exercise Medicine (SEM), University of Parma School of Medicine, c/o Maggiore Hospital, Parma, Italy
Roberto Toni
Museum of Biomedicine and Historical Laboratory (BIOMED), University of Parma Museum Network System, Parma, Italy
Roberto Toni
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA
Roberto Toni

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Ronald M. Lechan
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Knarik Arkun
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Roberto Toni
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Correspondence to Ronald M. Lechan .

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Editors and Affiliations

Neuroendocrine and Pituitary Clinical Center, Massachusetts General Hospital, Boston, MA, USA
Nicholas A. Tritos
Neuroendocrine and Pituitary Clinical Center, Massachusetts General Hospital, Boston, MA, USA
Anne Klibanski

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Lechan, R.M., Arkun, K., Toni, R. (2019). Pituitary Anatomy and Development. In: Tritos, N., Klibanski, A. (eds) Prolactin Disorders. Contemporary Endocrinology. Humana, Cham. https://doi.org/10.1007/978-3-030-11836-5_2

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DOI: https://doi.org/10.1007/978-3-030-11836-5_2
Published: 07 May 2019
Publisher Name: Humana, Cham
Print ISBN: 978-3-030-11835-8
Online ISBN: 978-3-030-11836-5
eBook Packages: MedicineMedicine (R0)

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Pituitary Anatomy and Development

Abstract

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Pituitary Gland Embryology, Anatomy and Physiology

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The Pituitary Gland: Functional Relationship with the Hypothalamus, Structure, and Physiology

Keywords

Historical Anatomy

Macroscopic Anatomy

Landmarks of the Sellar Region

Pituitary Gland

Vascularization of the Pituitary Gland

Embryologic Anatomy

Radiologic Anatomy

Microscopic and Functional Anatomy

Anterior Pituitary (Adenohypophysis)

Pars Distalis

Pars Intermedia

Marginal Zone

Pars Tuberalis

Posterior Pituitary

Concluding Remarks

References

Acknowledgements

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Pituitary Anatomy and Development

Abstract

Similar content being viewed by others

Pituitary Gland Embryology, Anatomy and Physiology

Pituitary Gland

The Pituitary Gland: Functional Relationship with the Hypothalamus, Structure, and Physiology

Keywords

Historical Anatomy

Macroscopic Anatomy

Landmarks of the Sellar Region

Pituitary Gland

Vascularization of the Pituitary Gland

Embryologic Anatomy

Radiologic Anatomy

Microscopic and Functional Anatomy

Anterior Pituitary (Adenohypophysis)

Pars Distalis

Pars Intermedia

Marginal Zone

Pars Tuberalis

Posterior Pituitary

Concluding Remarks

References

Acknowledgements

Author information

Authors and Affiliations

Corresponding author

Editor information

Editors and Affiliations

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Copyright information

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