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Home , Anterior pituitary, Herring bodies, Pituicyte, Pituitary gland, Pituitary stalk, Posterior pituitary

1 THE NORMAL PITUITARY

The adenohypophysis is a red-brown epithelial GROSS gland; the neurohypophysis is a firm gray neural The human , or hypophysis, structure that is composed of of hypo- is a small bean-shaped that lies in the thalamic and their supporting stroma , or hypophysial fossa, a concave (figs. 1-4, 1-5). structure in the superior aspect of the sphenoid The adult human pituitary gland measures at the base of the (figs. 1-1–1-3). approximately 13 mm transversely, 9 mm The gland is well protected by the bony sella. anterior-posteriorly, and 6 mm vertically. It Lateral to the sella are the cavernous sinuses, weighs approximately 0.6 g. The female gland is which contain the internal carotid and somewhat larger than the male gland; this can the oculomotor, trochlear, abducens, and first be documented on magnetic resonance imag- division of the trigeminal ; inferior and ing (MRI) where a difference of up to 2 mm in anterior is the ; superior is the height is seen (1,2). The pituitary gland of preg- ; and superoanterior is the optic nant and postpartum women is larger (1,3) and chiasm. The bilaterally symmetric gland has heavier (4); the increased size is due to marked two parts: the adenohypophysis and the neuro- cell hyperplasia during and hypophysis. As their names suggest, these two , which increases the weight to 1 g or parts are structurally and functionally different. more. Postlactational involution occurs but the

Figure 1-1 ANATOMY OF THE PITUITARY GLAND Sagittal section through the midline shows the pituitary gland within the sella turcica, attached to the hypothalamus by the . The gland is situated immediately posterior to the sphenoid sinus. (Section I, plate 4 from Netter FH, Forsham PH, eds. and selected metabolic diseases. The CIBA collection of medical illustrations, Vol 4. New York: Colorpress; Switzerland: CIBA; 1970:6.)

1 Tumors of the Pituitary Gland

Figure 1-2 ANATOMY OF THE PITUITARY GLAND A view of the base of brain shows the pituitary gland immediately posterior to the optic chiasm and anterior to the . (Section I, plate 4 from Netter FH, Forsham PH, eds. The CIBA collection of medical illustrations, Vol. 4. Endocrine system and selected metabolic diseases. New York: Colorpress; Switzerland: CIBA; 1970:6.)

Figure 1-3 ANATOMY OF THE PITUITARY GLAND Frontal section shows the pituitary gland in relationship to the cavernous sinuses and their contents. (Section I, plate 5 from Netter FH, Forsham PH, eds. The CIBA collection of medical illustrations, Vol. 4. Endocrine system and selected metabolic diseases. New York: Colorpress; Switzerland: CIBA; 1970:7.)

2 The Normal Pituitary Gland

Figure 1-4 NORMAL PITUITARY GLAND The anterior lobe is composed of tan soft tissue (left) and the posterior lobe of firm white tissue (right). The pituitary stalk is at the top. (Fig. 1-4 from Fascicle 22, Third Series.)

Figure 1-5 NORMAL PITUITARY GLAND Horizontal cross section shows the anterior lobe, composed of tan soft tissue (bottom); the posterior lobe, composed of firm white tissue (top); and cysts of the remnant intermediate lobe between them.

gland does not return to its pregestational size. eminence, or infundibulum; the neural stalk, or The of multiparous women are heavier infundibular stem; and the posterior lobe of the than those of nulliparous women (5). There is pituitary, or infundibular process. a slight to moderate size and weight reduction The adenohypophysis comprises about 80 with advancing age in both (1,3). percent of the pituitary gland. It is composed of The neurohypophysis is composed of three parts: the pars distalis, the , fibers from hypothalamic nuclei that project and the (fig. 1-6). The pars distalis downward. These give rise to the median is the largest portion of the gland; it is generally

3 Tumors of the Pituitary Gland

Figure 1-6 ANATOMIC COMPONENTS OF THE PITUITARY GLAND (Fig. 1-6 from Fascicle 22, Third Series.) known as the anterior lobe or the pars glandu- 5 percent of patients have hyperprolactinemia laris. The pars intermedia, or intermediate lobe, which may be caused by a coexistent prolactin- is rudimentary in the human pituitary; it is the producing pituitary but is often idio- vestigial posterior limb of the Rathke pouch (see pathic and has been attributed to distortion of the ) and is found in an underdeveloped infundibular stalk and reduction in hypothalamic form adjacent to the residual cleft of the pitu- tonic inhibition (9). itary. The pars tuberalis is an upward extension Other minor anatomic variations in the size of the adenohypophysial cells that surround the and shape of the pituitary gland and its relation lower hypophysial stalk (6); it is also known as to surrounding structures appear to have no the pars infundibularis. endocrine significance (4). The hypophysis is enveloped by , Vascular Supply a layer of dense connective tissue that lines the sella turcica. The , a reflection The blood supply of the human pituitary of the dura that constitutes the roof of the sella gland is a complex portal system that originates turcica, has a small central opening for the hy- in the hypothalamus (fig. 1-11). This hypophy- pophysial stalk, the connection to the hypothala- sial portal circulation carries hypothalamic mus (fig. 1-7). The sellar diaphragm protects the stimulatory and inhibitory from the pituitary gland from the pressure of cerebrospinal infundibulum to adenohypophysial cells, there- fluid (CSF). Defective development or absence of by playing a major role in the regulation of ad- this structure causes the in enohypophysial secretion (10–15). which increased CSF pressure results in enlarge- The arterial supply of the ment of the sella turcica and compression of the and is derived from two pituitary gland (figs. 1-8–1-10). In severe cases, or, in some individuals, three paired arteries the entire gland is only a thin layer of tissue at which arise from the intracranial portions of the bottom of the sella turcica. This lesion is usu- the internal carotid arteries: superior, middle, ally unassociated with functional hypophysial and inferior hypophysial arteries. The superior abnormalities (7,8), however, approximately hypophysial arteries branch into an external

4 The Normal Pituitary Gland

Figure 1-7 NORMAL DIAPHRAGMA SELLAE Normal sella turcica viewed from above shows an intact dia- phragm and pituitary gland with the pituitary stalk emerging from the sellar diaphragm. (Fig. 1-7 from Fascicle 22, Third Series.)

Figure 1-8 EMPTY SELLA SYNDROME Magnetic resonance imaging (MRI) identifies an enlarged sella turcica (arrows) in which the pituitary parenchyma is compressed at the bottom; the space is filled with cerebrospinal fluid (left, sagittal view; right, coronal view). (Courtesy of Dr. S. Ezzat, Ontario, Canada.) and an internal plexus. The external plexus is of a central muscular surrounded by composed of small arteries which surround the a spiral of ; the feeds the upper half of the stalk and give rise to a mesh capillaries through small orifices surrounded of capillaries. The internal plexus forms the by muscular sphincters. Flow through these gomitoli, unique vascular structures, 1 to 2 mm complex structures in the infundibulum and in length and 0.1 mm in width, composed proximal hypophysial stalk proceeds through

5 Tumors of the Pituitary Gland

Figure 1-9 EMPTY SELLA SYNDROME A widely opened sellar dia- phragm allows increased pressure from cerebrospinal fluid within to compress the pituitary. (Fig. 1-9 from Fascicle 22, Third Series.)

Figure 1-10 EMPTY SELLA SYNDROME The pituitary gland is atten- uated along the bottom of the enlarged sella. (Fig. 1-10 from Fascicle 22, Third Series.)

the portal vessels to adenohypophysial capillar- nal surface of the pituitary stalk in the subarach- ies. Although their function is not certain, the noid space and give rise to the subcapsular artery complexity of these gomitoli suggests that they and the artery of the fibrous core. These arteries regulate the rate of blood flow to the anterior provide a minor contribution to the blood sup- pituitary gland, thereby influencing the trans- ply of the adenohypophysis, then return upward port of hypothalamic regulatory hormones to along the pituitary stalk as the long stalk arteries the adenohypophysis. In some individuals, the to anastomose with the neurohypophysial capil- middle hypophysial arteries form the trabecular, lary bed. The inferior hypophysial arteries enter or loral, arteries, which descend along the exter- the sella turcica just beneath its diaphragm and

6 The Normal Pituitary Gland

Figure 1-11 BLOOD SUPPLY OF THE HYPOTHALAMUS AND PITUITARY (Plate XVII from Scheithauer BW. The hypothalamus and neurohypophysis. In: Kovacs K, Asa SL, eds. Functional endocrine pathology. Boston: Blackwell Scientific; 1991:170-244.)

supply the pituitary capsule, the neural lobe, occurs within the neurohypophysial and the lower pituitary stalk. In the intralobar bed, resulting in the mixing of blood derived groove, they divide into ascending and descend- from different portal vessels (14,15). The adeno- ing branches, which form an arterial circle about hypophysis receives the majority of its blood the neural lobe. A branch to the lower pituitary from portal vessels via the neural lobe, but, stalk, the communicating artery, anastomosis in addition, some arterial blood is directed to with the trabecular arteries. The capillaries of the adenohypophysis via two branches of the the neurohypophysis are fenestrated and lie inferior hypophysial artery: the capsular artery, outside the blood-brain barrier. which supplies the connective tissue of the Early studies suggested that the long portal pituitary capsule and penetrates to the superfi- vessels that arise in the infundibulum carry cial cell rows of the adenohypophysis, and the 70 to 90 percent of the pituitary blood flow artery of the fibrous core. In some individuals, while only 10 to 30 percent originates in the the middle hypophysial artery vascularizes the short portal vessels that link the infundibular adenohypophysis directly (16). stem or process to the adenohypophysis (13). The venous drainage of the pituitary gland It is now recognized, however, that blood flow is to the and from there to the

7 Tumors of the Pituitary Gland

inferior petrosal sinuses bilaterally. The volume where the hormones are released into the hy- of the leading away from the adenohy- pophysial portal vascular system. pophysis and neurohypophysis to the cavern- ous sinus is considerably less than that of portal EMBRYOLOGY vessels entering the gland. This observation led The adenohypophysis derives from the to the recognition of the neurohypophysial cap- Rathke pouch, an endodermal invagination of illary bed as a dynamic pool in which the short the primitive oral cavity. At the third week of portal vessels also serve as efferent channels. gestation, endoderm from the roof of the sto- The reversal of blood flow in this system implies modeum thickens and begins to invaginate; by that secretory products of the adenohypophysis 5 weeks, the Rathke pouch is a long tube with enter the neurohypophysis and the median a narrow lumen and a thick wall composed of eminence and can play a role in the regulation stratified cuboidal epithelium (fig. 1-12). By 6 of hypothalamic functions (14,15). weeks, the connection with the oropharynx Pituitary capillaries are lined by fenestrated is totally obliterated and the Rathke pouch endothelium with a thin subendothelial space. establishes direct contact with the downward Hormones released by adenohypophysial cells extension of the hypothalamus that gives rise to pass through the basement membrane of their the infundibulum. The two tissues are enclosed cell of origin, capillary basement membrane, by the anlage of the , subendothelial space, and endothelial cell layer separating them from the , and the to reach the bloodstream. sella turcica is formed by 7 weeks (19). It has been suggested that the Rathke pouch Nerve Supply arises from the ventral neural ridge in the The nerve supply of the pituitary gland is pharyngeal region, thus sharing with the hy- unique and crucial to the regulation of pituitary pothalamus and posterior pituitary a common function (17). Despite this fact, the human neuroectodermal origin (20,21). The use of adenohypophysis has no direct nerve supply, avian allografts, biological markers, and serial apart from small sympathetic nerve fibers that sections of early chick embryos provided indi- are associated with, and presumably innervate, rect evidence for this theory. capillaries. Thus, neural connections may affect Adenohypophyseal development and cyto- blood flow to the adenohypophysis but appar- differentiation are regulated by highly specific ently have no direct role in the regulation of transcription factors (22–24). The Rathke pouch adenohypophysial hormone secretion. homeobox (Rpx) protein (also known as Hesx1), The posterior lobe, in contrast, is composed Pax-6, the bicoid-related pituitary homeobox almost exclusively of axons and nerve fibers that factor 1 (Ptx1), and structurally related pituitary arise from the hypothalamus. It is these neural homeobox factor 2 (Ptx2) are all required for connections that are required for the normal early pituitary organogenesis. Two members of secretion of the two hormonal products of the the LHX gene family, a group of LIM homeobox posterior pituitary, and genes, LHX3 and LHX4, and P-LIM, another (antidiuretic hormone [ADH]), as well as for LIM homeobox protein transcription factor, are the transport of the other hypothalamic pep- expressed in the pituitary, with highest levels at tides that regulate adenohypophysial function the early stages of Rathke pouch development (17,18). (25). Another early determinant of pituitary dif- The hypothalamo-hypophysial tract, consisting ferentiation is the Prophet protein of pituitary primarily of nerve fibers from the supraoptic transcription factor-1 (Pit-1) (PROP-1); this and paraventricular nuclei, carry vasopres- paired-like homeodomain protein is expressed sin and oxytocin to the posterior lobe of the early in pituitary development (26). It induces pituitary, where the hormones are released expression of the next phase of development di- into capillaries. The tubero-infundibular tract, rected by the pituitary transcription factor Pit-1, originating from neurosecretory neurons that and plays a role in the downregulation of Rpx, produce hypophysiotropic hormones, projects which is required for cell differentiation. Id, a from several nuclei to the median eminence member of the helix-loop-helix (HLH) family

8 The Normal Pituitary Gland

the pars nervosa reverses the convexity of the posterior wall of the cleft to a concave structure. The border between the Rathke pouch and the pars nervosa becomes indistinct; it consists of remnants of the obliterating lumen, a few cystic cavities lined by cuboidal or columnar epithelium. This represents the rudimentary pars intermedia of the human hypophysis. The pituitary gland grows rapidly in early fetal life: the mean weight at 10 to 14 weeks of gestation is 3 mg; at 25 to 29 weeks, 50 mg; and at term, approximately 100 mg (27,28). The pituitary portal vascular system begins to form before 7 weeks of gestation and by 12 weeks the and median eminence are well vascularized. Portal vessels are recognized at 11.5 to 14.0 weeks, are well developed by 15 to 16 weeks, and are fully established by 18 to 20 weeks (29,30). Remnants of the developing adenohypophy- sis may be deposited along the route followed by the Rathke pouch. The most common site is the roof of the nasopharynx; this “pharyn- geal pituitary” is found in most individuals (31,32). It contains all the hormone-producing cell types found in the normal gland and is thought to have transsphenoidal vascular con- Figure 1-12 nections to the sellar hypophysis to maintain RATHKE CLEFT IN A FETUS homeostatic feedback mechanisms (33). Ectopic AT 5 WEEKS OF GESTATION adenohypophysial tissue has also been described Columnar cells line the Rathke cleft and the connection in a suprasellar location in up to 20 percent of with the stomodeum (S) has been obliterated. Blood vessels (arrows) adjacent to the primitive (D) and people (34). These ectopic foci are usually of the pituitary anlage are the precursors of the hypophysial incidental interest only, but they may be the portal system. (Fig. 1a from Asa SL, Kovacs K, Functional site of adenoma formation that can confound morphology of the human fetal pituitary. Pathology Annual the clinical diagnosis (35,36) or they may be 1984;9(Pt 1):275-315.) detected with sophisticated imaging techniques and mimic a tumor (37). rests are of transcription factors; Isl-1, a LIM factor; and common if carefully sought, and are thought to several other transcription factors are also ex- be continuous with the Rathke cleft (38,39). pressed early in pituitary development. Aplasia of the pituitary gland is usually associ- As the cells of the Rathke pouch proliferate, ated with severe congenital malformations. It the anterior portion forms the pars distalis and forms part of the Cornelia de Lange syndrome, pars tuberalis while the posterior wall lies in di- also known as Brachmann−de Lange syndrome, rect contact with the posterior lobe anlage and a genetically heterogeneous disorder affecting becomes the pars intermedia (19). The growth of multiple aspects of development due to sporadic the anterior limb extends laterally and follows dominant mutations in one of several genes, a triradiate pattern; the lateral borders become all of which are involved in sister chromatid the lateral wings of the adult gland and the cohesion (40).Itisalsoassociatedwiththe. It is also associated with the midline portion becomes the anteromedial Arnold-Chiari malformation (41). One form mucoid wedge. By midgestation, the medial of this disorder associated with septo-optic cleft becomes a residual lumen and growth of dysplasia has been attributed to mutation of

9 Tumors of the Pituitary Gland

RPX1/HESX1 (42) or of the SOX2 gene (43). specified and differentiated, but an early period Aplasia or hypoplasia may be associated with of increased cell death and reduced proliferation evidence of , including adrenal causes reduced growth, affecting corticotrophs and aplasia or hypoplasia (44–48). and somatotrophs (62,63). The identical pat- Dystopia of the gland is the result of failure tern of maldevelopment results from deletion of union of the adenohypophysis and neurohy- of the Ikaros gene that regulates pituitary cell pophysis (49). Duplication of the pituitary gland population expansion, primarily affecting has also been reported, usually in association corticotrophs and somatotrophs (64,65). This with other craniofacial malformations (50). epigenetic regulator appears to play a key role Given the role of several of these transcrip- in determining cell proliferation and apoptosis tion factors in pituitary gland development, it (66) and is implicated in pituitary tumorigenesis is not unexpected that mutations of the genes (67) as well as other aspects of neuroendocrine encoding critical factors are implicated in hy- and immune development and disease (68). popituitarism. LHX3 mutations are identified in patients with combined pituitary hormone MICROSCOPIC AND deficiency, including deficiencies of growth FUNCTIONAL ANATOMY hormone (GH), prolactin (PRL), thyroid-stimu- Hypothalamus and Neurohypophysis lating hormone (TSH), and luteinizing hor- mone/follicle-stimulating hormone (LH/FSH) The hypothalamic nuclei that give rise to (51,52). Mutations of LHX4 are rarer but also the neurohypophysis are divided into four result in pituitary hormone deficiencies (53,54). anatomic areas: the preoptic, supraoptic-lat- Inactivating mutations of PROP-1 also result in eral, tuberal, and mamillary regions (fig. 1-13). combined pituitary hormone deficiency (55,56). Whereas the nuclei are topographically discrete Pituitary dwarfism with occurs in many species and may be demarcated in the in patients with mutations of the PIT-1 gene (57- human fetus, they are poorly defined in the 59), likely due to hypoplasia of somatotrophs, mature human hypothalamus (17). Structure- lactotrophs, and thyrotrophs (60). These various function correlations are difficult because of the mutations are rare and in nearly all cases, the cellular heterogeneity of many hypothalamic clinical manifestations are due to homozygous nuclei. Any given hypothalamic hormone is mutations in consanguineous families. often produced in more than one nucleus, and, The expansion of differentiated cell popu- in many cases, a single nucleus expresses more lations is dependent on a number of factors, than one hormone. The physiologic roles of including hypothalamic trophic hormones and many nuclei remain unknown. Nevertheless, target organ hormonal feedback and growth this area is responsible for the production of the factors. Anencephalic fetuses provide an inter- neurohypophysial hormones, oxytocin and va- esting experiment of : the adenohypo- sopressin (ADH), and for the hypophysiotropic physial cells differentiate and the transcription hormones that are released into the hypophysial factors implicated in cytodifferentiation are portal vasculature and regulate adenohypo- expressed in the absence of a hypothalamus, physial function, including - but the pituitaries are small and have reduced releasing hormone (GHRH), (SST, numbers of gonadotrophs and corticotrophs, also known as somatotropin release-inhibiting indicating the importance of hypothalamic hormone [SRIH]), and other putative factors in promoting expansion of those cell prolactin-inhibiting substances, corticotropin- populations (61). Other factors also regulate releasing hormone (CRH), thyrotropin-releas- the expansion of differentiated cell popula- ing hormone (TRH), -releasing tions. Several members of the Notch signaling hormone (GnRH), and numerous other pathway are expressed in the developing gland that affect adenohypophysial function (17). and deletion of the Notch signaling target The most anterior nuclei are the paired me- transcription factor Hes- (hairy and enhancer dial and lateral nuclei that are associated with of split-1) is associated with pituitary anterior autonomic function, particularly temperature lobe hypoplasia. All cells in the anterior lobe are control and olfaction. The suprachiasmatic

10 The Normal Pituitary Gland

Figure 1-13 HYPOTHALAMIC REGION AND PITUITARY: NUCLEI AND MAIN FIBER TRACTS (Plate XVIII from Scheithauer BW. The hypothalamus and neurohypophysis. In: Kovacs K, Asa SL, eds. Functional endocrine pathology. Boston: Blackwell Scientific; 1991:170-244.)

nucleus, in the dorsal to the optic associated with fibers of the supraoptic commis- chiasm and anterior to the , sure, and receives afferents from the retina and is essential for gonadotropin release and sexual the lateral geniculate bodies. The anterior hypo- behavior in lower animals. This sexually dimor- thalamic nucleus is composed of small neurons phic nucleus, which decreases in volume and which mediate parasympathetic effects. cell number with age, is thought to play a role The lateral hypothalamic nuclei are composed in the sexual differentiation of the brain which, of large neurons which receive fibers from and in the absence of male gonadal hormones, re- contribute efferents to the median mains female but, if exposed to male gonadal bundle. The paraventricular nuclei, which are hormones at a critical stage in development, adjacent to the ventromedial becomes male (69,70). The role of gonadal ste- to the fornix, are composed mainly of large roids in regulating this sexual dimorphism has magnocellular neurons and contain a number been the subject of intense investigation and, of parvicellular neurons as well. The supraoptic interestingly, the evidence points to as nuclei, which overlie the optic tract, are the the primary determinant of masculinization fol- other paired magnocellular nuclei of the hypo- lowing the aromatization of testicular ; they have no significant parvicellular (71). The also plays a component. These nuclei are a major site of oxy- role in maintaining circadian rhythms (72); it is tocin and vasopressin synthesis; efferent fibers

11 Tumors of the Pituitary Gland

from these nuclei terminate in the posterior lobe nucleolar change considered a manifestation of of the pituitary gland. Patients with traumatic feedback effect, likely due to a lack of or surgical stalk section and those with long- (81,85,86), which is also observed in neurons standing hypopituitarism have atrophy of these of the (82). nuclei, with a marked reduction in the number The tuberal nuclei, irregularly grouped masses of magnocellular neurons and stalk nerve fibers of large neurons inferior to the lateral nuclei, give (73,74); the parvicellular component of the rise to efferent fibers of the hypothalamus; after paraventricular nuclei remains. stalk section, they exhibit a slight increase in The dorsomedial and ventromedial nuclei, coarsely granular basophilic cytoplasmic material situated between the tuber cinereum and para- (87). The posterior hypothalamic nucleus, situated ventricular nuclei, are involved in autonomic between the third ventricle and the mamillo- function, hunger and satiety, and emotional thalamic tract superior to the mamillary bodies, behavior. Stimulation of the dorsomedial and produces sympathetic effects when stimulated. destruction of the ventromedial nuclei produce It has been implicated in temperature regula- in experimental animals. Destruction of tion and its large neurons are thought to be the the ventromedial nucleus results in obesity source of hypothalamic efferents which descend (75); conversely, destruction of the ventrolateral to the reticular formation of the brainstem. nucleus, known as the “feeding center,” causes The paired mamillary nuclei and other minor anorexia and cachexia (76). These nuclei have nuclei in the supramamillary area, including the afferent connections from olfactory and retinal nucleus intracalatus, form the posterior hypothala- fibers, the reticular formation, and the nucleus mus. These nuclei integrate incoming information of the solitary tract, which receives input from from the limbic system and the midbrain tegmen- the vagus. Afferents from the cortex enter by tum and send out efferent fibers to the anterior way of the thalamus. The discovery of , thalamic nucleus and the brainstem. an adipose-derived hormone (77,78), led to the The neurohypophysis is composed of nerve identification of the mechanisms by which the fibers, terminals, and stromal cells or pitui- mediobasal hypothalamus controls food intake cytes, modified thought to originate from the and energy expenditure in these and other hy- ependyma (fig. 1-14). The dilated axonal termi- pothalamic nuclei. Specific cell types respond nals are recognized on routine hematoxylin and to leptin through well-characterized signaling eosin (H&E)–stained sections as acidophilic glob- cascades that mediate its effects (79). ules known as . The neural elements Ventral to the third ventricle and paraventric- contain neurosecretory material, which can be ular nuclei is the arcuate (infundibular) nucleus, demonstrated histologically with the Gomori which is another important component of the chromalum hematoxylin, aldehyde fuchsin, and hypophysiotropic region and plays a major aldehyde thionin stains (fig. 1-15). Immunohisto- role in the modulation of anterior pituitary chemistry reliably detects the neuronal elements function. This nucleus contains proopiomela- with -specific enolase (NSE) or neurofila- nocortin neurons that also play an important ment antibodies, with antibodies to glial role in the integration of leptin signaling to fibrillary acidic protein (GFAP) or S-100 protein, control obesity and through pi- and the neurosecretory material with antisera to tuitary signals (79). The subventricular nucleus, oxytocin, vasopressin (fig. 1-16), and their carrier on the floor of the third ventricle posterior to proteins, the . The ultrastructural the arcuate and anteromedial to the tuberal features of the neurohypophysis (fig. 1-17) have nuclei, is a parvicellular nucleus which under- been described in detail (88–91). goes marked hypertrophy to become a mag- Adenohypophysis nocellular nucleus in postmenopausal women (80,81), in young women with postpartum The cell types of the adenohypophysis are hypopituitarism with gonadal atrophy (82), in highly characterized with respect to structure hypogonadal men and women, in starvation and function. Although acidophils, baso- (83), after (84), and in late phils, and chromophobes are recognized with pregnancy. The neurons develop a distinctive conventional H&E staining (fig. 1-18) and a

12 The Normal Pituitary Gland

Figure 1-14 Figure 1-15 POSTERIOR LOBE OF THE PITUITARY POSTERIOR LOBE OF THE PITUITARY The posterior lobe is composed of nerve fibers and pituicytes, Neurosecretory material is identified with the aldehyde modified glial cells. The neurons have dilated eosinophilic thionin stain in axonal terminals of the posterior lobe. (Fig. nerve terminals known as Herring bodies (arrow). 1-14 from Fascicle 22, Third Series.)

Figure 1-16 POSTERIOR LOBE OF THE PITUITARY Immunohistochemistry local- ized vasopressin (ADH) in nerve fibers and in axonal terminals.

13 Tumors of the Pituitary Gland

Figure 1-17 Figure 1-18 POSTERIOR LOBE OF THE PITUITARY NORMAL PITUITARY Electron microscopy shows a (a glial cell of Hematoxylin and eosin (H&E) stain shows acini of the posterior lobe) associated with neuronal processes adenohypophysial cells. Acidophils have orange-red containing neurosecretory granules, including a markedly cytoplasm; basophils have purple-blue granular cytoplasm dilated nerve ending known as a Herring body. (Fig. 1-15 and contain clear vacuoles (arrows), corresponding to the from Fascicle 22, Third Series.) “enigmatic body” of corticotrophs. Scattered among these are chromophobic cells with clear to pale pink cytoplasm. number of specialized histochemical stains tuberalis. Within the pars distalis itself, there have been devised to identify individual cell are three distinct anatomic areas, the central types, accurate classification is based on both mucoid wedge and the two lateral wings, that immunohistochemical localization of hormone can be readily recognized on horizontal cross products and ultrastructural morphology. The section of the gland (fig. 1-19). use of immunocytochemistry at the electron The molecular factors that determine cell microscopic level allows correlation between differentiation and hormone production in these two methods of characterizing adenohy- adenohypophysial cells are the transcription pophysial cells. It is therefore possible to discuss factors that target specific hormone genes. These the known cell types and their major hormonal factors have clarified three main pathways of function (Table 1-1). cell differentiation (fig. 1-20) (22,23). The distribution of the various cell types in Somatotrophs, lactotrophs, mammo- the adenohypophysis is not even. Each cell somatotrophs, and thyrotrophs all derive from population is found in different proportions GH-producing precursors that express the in the pars distalis, pars intermedia, and pars pituitary transcription factor-1 (Pit-1) (92,93),

14 The Normal Pituitary Gland

Table 1-1 CLASSIFICATION OF PITUITARY CELLS AND HORMONAL PRODUCTS

Cell Type Transcription Factors Hormone Gene Expression Hormone Product(s) Corticotroph Tpita ACTH Ptx1 b-endorphin neuroD1 MSH Other POMC-derived peptides Somatotroph Pit-1 GH GH a-subunit a-subunit Mammosomatotroph Pit-1 GH GH ERa PRL PRL a-subunit a-subunit Lactotroph Pit-1 PRL PRL ERa Thyrotroph Pit-1 a-subunit TSH TEF b-TSH GATA-2 Gonadotroph SF-1 a-subunit FSH ERa b-FSH LH GATA-2 b-LH aTpit = T-box transcription factor; ACTH = adrenocorticotropic hormone; MSH = melanocyte-stimulating hormone; LH = ; POMC = proopiomelanocortin; PRL = prolactin; Pit = pituitary transcription factor; TSH = thyroid-stimulating hormone; TEF = thyrotroph embryonic factor; GH = growth hormone; SF = steroidogenic factor; ER = receptor; FSH = follicle-stimulating hormone. a 291- protein that belongs to the A putative thyrotroph-specific factor has been homeobox family of developmental regulatory described. Thyrotroph embryonic factor (TEF) is a proteins. Pit-1 binds the promoter sequences trans-acting factor that belongs to the leucine and activates the structurally related GH and zipper gene family of transcription factors; it is PRL genes in rat and human (94). In addition, thought to activate the expression of the human the gene encoding the beta-subunit of TSH b-TSH gene (101). GATA-2 (a member of the fam- contains sites that bind Pit-1, although with ily of transcription factors characterized by their lower affinity than sites in the GH or PRL gene ability to bind to the DNA sequence “GATA”) 5’-flanking regions (95). The PIT-1 gene is selec- appears to be an important contributor to thy- tively expressed in adenohypophysial cell types rotroph development (102). Mature thyrotrophs responsible for GH, PRL, and b-TSH synthesis also suppress GH production (24). This Pit-1 family (92,93,96). Differentiation and maintenance of cells is thought to maintain fluidity so that in of somatotroph, lactotroph, and thyrotroph various situations there is transdifferentiation: phenotypes are dependent on expression of a somatotrophs convert to mammosomatotrophs functional PIT-1 gene; mutations in this gene and lactotrophs during pregnancy, and to result in hypopituitarism (58–60). thyrotrophs in hypothyroidism. These are thought Expression of estrogen receptor-alpha (ERa) to be reversible transdifferentiation processes. correlates with expression of PRL or gonado- The expression of proopiomelanocortin tropins (97–99); this cell-specific expression (POMC) that defines corticotrophs is dependent suggests that ERa may be the factor responsi- on the T-box transcription factor, Tpit (103). Mice ble for the development of PRL expression in deficient of Tpit have isolated adrenocortico- Pit-1-expressing somatotrophs. ERa enhances (ACTH) deficiency similar to PRL secretion (100), allowing mammosoma- the rare human condition of childhood-onset totroph differentiation. A silencing mechanism ACTH deficiency, which has also been associ- is thought to repress GH production to allow ated with inactivating mutations of this gene mature lactotrophs to develop. (104). Tpit interacts with Ptx1 (105) and proteins

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