II.      Anatomy of the Pituitary Gland

A. Gross and Radiologic Anatomy

    The pituitary gland lies within a recess of the median part of the middle cranial fossa in the sphenoid bone (sella turcica) and is composed of two major components, the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis) that can be readily distinguished radiologically by magnetic resonance imaging (Fig. 5).  The anterior lobe contains three subdivisions including the pars distalis, pars intermedia and pars tuberalis.  The pars distalis makes up the bulk of the anterior pituitary and is primarily responsible for the secretion of anterior pituitary hormones into the peripheral circulation.  The pars intermedia lies between the pars distalis and the posterior pituitary and is vestigial in man, while the pars tuberalis is well defined in most mammalian species and surrounds the infundibular stem (7).  The floor of the sella, or lamina dura, abuts the sphenoid sinus, allowing direct surgical access to the pituitary by the transsphenoidal route.  Other important boundaries to the pituitary gland are the cavernous sinus laterally, which contain the internal carotid artery surrounded with sympathetic fibers, and the cranial nerves III, IV, V (ophthalmic and maxillary branches), and VI (Fig. 6).  The optic chiasm is located superiorly, separated from the pituitary by the cerebrospinal fluid-filled suprasellar cistern and the dural roof of the pituitary, the diaphragma sella.

Fig. 5. (A) Magnetic resonance image (MRI) and (B) corresponding schematic illustration of the human hypothalamus (H) and pituitary gland seen in saggital orientation.  Note the high intensity or "bright spot" of the posterior pituitary by MRI in (A), sharply defining the boundary between the anterior pituitary gland.  III = third ventricle (Modified from Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation.  Endocrinology and Metabolism Clinics 16:475-501, 1987.)

B. Embryologic Anatomy

 The posterior lobe of the pituitary gland is smaller than the anterior lobe and embryologically derives from the neural primordia as an outpouching from the floor of the third ventricle.  As a direct, anatomic extension of the central nervous system, it is not surprising that the posterior pituitary is composed primarily of unmyelinated axons and axon terminals as well as specialized glial cells called pituicytes.

    In contrast to the posterior pituitary, the anterior pituitary derives from the oral ectoderm as Rathke's pouch, first seen by the third week of pregnancy in man, and gives rise to both the pars distalis and tuberalis.  There is little if any direct nervous innervation to the pars distalis, but cell to cell contact with the neuroectoderm of the primordium of the ventral hypothalamus is critical for differentiation of the anterior pituitary into the five major cell types.  This occurs as a result of the release of specific growth and transcription factors such as bone morphogenic protein (BMP)-4 and fibroblast growth factor (FGF)-8 (8).  Among the numerous transcription factors involved in positional determination and terminal differentiation of pituitary cell types (Fig. 7), the Notch signaling pathway serves a major role in mediating epigenetic regulation of lineage commitment through activation of non-coding RNAs and chromatin-histone interactions (9,10).  Recent evidence has also indicated a key role for SOX 2 and SOX3 in regulating pituitary morphogenesis both in rodent and man (11).  In humans, mutations of early transcription factors like Rpx, Prop-1 and Pit-1 lead to variable degrees of pituitary insufficiency (8).  Once the pituitary matures, the ability of the hypothalamus to communicate with the pars distalis is dependent upon the hypophysial portal system, a vascular link that connects the base of the hypothalamus to the pituitary gland.

Fig. 7.  Signaling molecules and transcription factors involved in the development of the mouse anterior pituitary from Rathke’s pouch.  In the anterior lobe somatotrophs, lactotrophs and caudally-placed thyrotrophs derive from a common lineage, determined by Prop-1 and Pit-1. Independent lineages are observed for a rostrally-placed group of thyrotrophs, corticotrophs, gonadotrophs and intermediate lobe melanotrophs.  All cell types are committed to a specific lineage through activation of Notch signalling at the placodal stage.  (Adapted from Cohen and Radovick, Endocrine Reviews 23: 431-442, 2002; Zhu X, Gleiberman AS, Rosenfeld MG, Physiol Rev 87:  933-963, 2007; Zhu X, Wang J, Ju B-G, Rosenfeld MG, Curr Op Cell Biol 19: 605-611, 2007).

C. Microscopic Anatomy

    Microscopically, the anterior pituitary is composed of nests or cords of cuboidal cells organized near venous sinusoids lined with a fenestrated epithelium into which secretory products from the anterior pituitary are collected.  Classically, five cell types and six secretory products of the anterior pituitary gland can be identified immunocytochemically including the somatotrophs (growth hormone), lactotrophs (prolactin), corticotrophs (adrenocorticotropic hormone), thyrotropes (thyroid-stimulating hormone), and gonadotrophs (luteinizing hormone and follicle-stimulating hormone) (12).  It is well recognized, however, that the anterior pituitary is vastly more complicated.  In addition to morphological and physiological evidence for heterogenity among the classical anterior pituitary cell types (13-16) and the presence of clusters of a unique cell type, the folliculostellate cell (17), the anterior pituitary can also synthesize numerous other nonclassical peptides, growth factors, cytokines, binding proteins and neurotransmitters listed in Table 2 that are important for paracrine and/or autocrine control of anterior pituitary secretion and/or cell proliferation under defined physiological conditions (18).  Pituitary stem cells have now been recognized in adult mammalian pituitaries as a group of Notch-, Shh-, Wnt- and Hes1-positive elements without hormonal production, primarily residing in the marginal zone around the pituitary cleft (19).  However, it is possible that more than a single stem cell type is present in the anterior pituitary.   In fact in rodents,  a number of cell groups with stemness potential have been identified, including a subpopulation of folliculostellate cells having the ability to form cell colonies in vitro, a heterogeneous SOX2-positive, SOX9-negative, sphere-forming cell population, a Nestin-positive, potentially adult, progenitor group, and GFRa2-positive (Glial cell line-derived neurotrophic Factor Receptor), sphere-forming cells with clear features of multipotent elements (20).

D. Blood Supply

    The pars distalis of the anterior pituitary gland receives little or no arterial blood supply from branches of the internal carotid artery (21,22), while the posterior pituitary is fed by an anastomotic arterial circle derived from each of the inferior hypophysial arteries as they pierce the cavernous sinus (Fig. 8).  Rather, the pars distalis is supplied by venous blood delivered through the long portal veins that descend along the ventral surface of the pituitary stalk and interconnect capillary beds in the pars distalis with specialized capillary beds of the portal capillary system in the base of the hypothalamus called the median eminence (Fig. 8).  In turn, the portal capillary plexus in the median eminence receives arterial blood from a separate branch of the internal carotid artery, the superior hypophysial artery, after the internal carotid artery ascends from the cavernous sinus.  In addition to venous blood draining from the hypothalamus, the pars distalis also receives venous blood draining from the posterior pituitary through the short portal vessels, giving rise to approximately 30 per cent of the total blood supply to the anterior pituitary (23,24).  The perfusion sequence of arterial blood first reaching the posterior pituitary and the median eminence, followed by venous drainage to the anterior pituitary can visualized in man using rapidly enhanced magnetic resonance images (dynamic MRI) (25) (Fig. 9).  As a result of the venous blood flow pattern to the pituitary, the pars distalis is in a unique position where it can receive humeral information from the hypothalamus and the posterior pituitary, as well as substances circulating in the peripheral bloodstream.  Due to the location of pars tuberalis cells in the pituitary stalk and ventral surface of the median eminence, adjacent to the portal capillary plexus, it is likely that these cells also contribute to the humeral substances that are carried by a vascular route to the pars distalis (26), although its physiological significance is unknown.

Fig. 8. Drawing of the vasculature of the primate anterior and posterior pituitary gland.  A portion of the pituitary stalk (I) has been cut away to visualize the infundibular recess (IR) and portal capillaries (PC).  CPV = confluent pituitary veins, CS = cavernous sinus, H = hypothalamus, IC = internal carotid artery, IHA = inferior hypophysial artery, IP = infundibular processes or posterior pituitary, LPV = long portal veins, SHA = superior hypophysial artery, SPV = short portal veins. (From Lechan RM, Functional Microanatomy of the Hypophysial-Pituitary Axis, in Melmed, S (Ed), Oncogenesis and Molecular Biology of Pituitary Tumors, Frontiers of Hormone Research, 20: 2-40, 1996.)

    Venous drainage from the anterior pituitary to the systemic circulation is through adenohypophysial veins located at a sulcus separating the anterior pituitary from the posterior pituitary (21).  Other than the short portal vessels, venous drainage from the posterior pituitary collects into neurohypophysial veins, which together with adenohypophysial veins, extend as common vessels (confluent pituitary veins) to the cavernous sinus (Fig. 8).