Macroscopic Features

The hypophysis occupies a bony recess in the basisphenoid (os basisphenoidale) (Fig. 4-18). The recess is a shallow, oval depression, the hypophyseal fossa (fossa hypophysials). The rostral and caudal margins of the fossa are formed by the rostral clinoid processes and the dorsum sella, respectively. When the fossa is viewed dorsally, the rostral and caudal clinoid processes accentuate the boundaries of the fossa on the dorsal surface of the basisphenoid bone referred to as the sella turcica. In the dog the fossa is quite shallow and is lined by the external, or endosteal, layer of dura mater. The inner, or meningeal, layer of the dura forms the diaphragma sellae. The latter does not pass directly into the fossa with the external dural layer but extends partially over the dorsal aspect of the fossa to provide an incomplete septum. The primary attachments of this septum, or diaphragm, are by way of the clinoid processes. A large oval foramen is present in the center of the diaphragm, which loosely encircles the stalklike connection of the hypothalamus to the hypophysis as it passes into the fossa. This thin meningeal layer then continues around the main portion of the gland as a delicate capsule. Schwartz (1936) demonstrated that the subarachnoid space does not invest the hypophysis.

The space created by the separation between the inner and outer dural layers contains prominent cavernous and intercavernous sinuses. Large cavernous sinuses bound the hypophysis laterally and are connected by intercavernous sinuses. The larger intercavernous sinus passes just caudal to the hypophysis. The smaller intercavernous sinus is present in only some individuals and, when present, it passes rostral to the hypophysis. The proximal portion of the middle meningeal artery and the anastomotic ramus of the external ophthalmic artery lie within each of the cavernous sinuses. The internal carotid artery also courses through each of the cavernous sinuses on the lateral margins of the hypophysis, from the dorsum sella rostral to the region of the optic chiasm. The oculomotor, trochlear, and abducent nerves and the ophthalmic nerve from the trigeminal nerve pass in close proximity to the hypophysis. The interpeduncular cistern is adjacent to the caudal aspect of the attachment of the hypophysis to the hypothalamus, and within the cistern lies the caudal part of the cerebral arterial circle (circulus arteriosus cerebri). A bony wall separates the hypophyseal fossa from the sphenoid sinus, which lies rostroventral to it. The positional relations of these structures to the hypophysis create a degree of surgical risk and, as reported by Harrison (1964) and emphasized by Farrow (1969), may account for many of the signs accompanying hypophyseal disease.

Mesoscopic Features

As noted by Hanström (1966), much of the literature demonstrates individual and breed differences in the morphologic characteristics of the hypophysis. The hypophysis of the adult (Figs. 10-1 and 10-2) has grossly visible rounded protuberances, the adenohypophysis and the neurohypophysis. The adenohypophysis, being composed of glandular parenchyma and having an extensive blood supply, appears reddened and friable in comparison with the pallor and the brainlike texture of the neurohypophysis. A median section of the hypophysis and the hypothalamus, when examined with slight magnification, reveals further subdivisions of the organ (Fig. 10-1). The gland is suspended from the midline of the hypothalamus by a cylindrical stalk. This stalk is an extension from the tuber cinereum of the hypothalamus. It is the proximal portion of the neurohypophysis, the infundibulum. In most dogs the third ventricle continues as an invagination into the infundibulum, a recess called the pars cava but it rarely passes into the more distal portion of the infundibulum. The distal compact infundibulum is continuous with the distal enlargement, the neural lobe (lobus nervosus) of the neurohypophysis, which is the modest expansion at the distal end of the infundibulum and the major portion of the neurohypophysis.

The principal axis of the gland is in a median plane. The largest portion of the adenohypophysis lies ventrorostral to the neural lobe, but it invests nearly all of the surface of this part of the neurohypophysis and forms three major subdivisions. The adenohypophysis contains a large, compressed vesicle, which, when seen in slices of the gland, appears as a cleft. It is termed the hypophyseal cavity (cavum hypophysis) and is a remnant of development of the stomodeal adenohypophyseal sac. The dorsal portion of the adenohypophysis is in direct contact with the neural lobe and is termed the pars intermedia adenohypophysis, owing to its location between the two major parts of the adenohypophysis. The largest portion of the adenohypophysis remains separated from the pars intermedia by the hypophyseal cavity and forms the distal portion of the adenohypophysis, pars distalis adenohypophysis. The adenohypophysis also extends as a cuff or collar around the infundibulum to envelop part of the tuber cinereum. This is the pars tunberalis adenohypophysis.

Developmental Anatomy

By the 7-mm stage of development in the dog, a small portion of oral ectoderm lining the dorsum of the stomodeum contacts the ventral surface of the neural tube. This contact or adhesion between oral and neural ectoderm is maintained while differential growth and the resultant proliferation of mesoderm continues in the head region. The neural ectoderm retains its relative position, and the adjacent portion of oral ectoderm is drawn away from the stomodeum, first as a cul-de-sac and then as a closed vesicle, saccus adenohypophysialis, separated from the developing oral cavity. With continued differentiation of the neural ectoderm, a small projection or evagination develops at the midline of the ventral surface of the diencephalon at the point of adhesion to the oral ectoderm. This structure, the sacculus infundibuli, becomes surrounded by the collapsing vesicle of oral ectoderm. The adjoining mesenchyme develops the stroma and vascularization for this parenchymal primordium of the hypophysis (Herring, 1908b; Kingsbury & Roemer, 1940; Latimer, 1965; Stockard, 1941).

This duality of origin results in an organ with segregated structure as well as function. The neural ectodermal portion forms the neurohypophysis with infundibulum and neural lobe. The vesicle of oral ectoderm invests the neurohypophyseal primordium on all of its surfaces except for a small area at the distal, caudal extremity. A portion of the vesicle extends to envelop the infundibulum. The surfaces of the vesicle contacting the neural lobe of the neurohypophysis develop into the pars intermedia adenohypophysis. The remaining portion of the vesicle, which does not directly contact the neurohypophysis, develops into the major glandular portions, the pars tuberalis adenohypophysis and the pars distalis adenohypophysis.

Microscopic Features

The general microscopic features of this gland are those of an endocrine gland and a segment of central nervous system tissue. The stroma is formed by a capsule of delicate pial connective tissues that forms around the neurohypophysis during development and remains as a boundary between it and the adenohypophysis subdivisions. The adenohypophysis is enveloped by a delicate investment of collagenous connective tissue of the arachnoid that binds the adenohypophysis to the adjoining inner layer of dura mater. At a point representing the original connection to the oral ectoderm on the midventral surface of the adenohypophysis, the adenohypophysis is attached to the inner dural layer, which is fused to the outer layer. This attachment is easily separated and usually accounts for some separation artifact in preparations of the pars distalis adenohypophysis. When a small remnant of development called the parahypophysis is present, it is attached at this location (Kingsbury & Roemer, 1940). The stroma that forms a capsule for both the neurohypophysis and the adenohypophysis is originally quite delicate and increases in amount only slightly with advancing age. The blood vessels are invested by small amounts of adventitial connective tissues, and the parenchymal cells of the adenohypophysis are supported by a delicate interstitium of reticular fibers.

The pars distalis adenohypophysis has a parenchyma of epithelioid cell types arranged in small, interconnected clusters, racemi endocrinocyti, that are bounded and permeated by numerous sinusoids. These aggregates of cells are quite varied in size and shape and are arranged three-dimensionally as anastomosing lattices. The close proximity of nearly all parenchymal cells to a sinusoid is maintained throughout. By the use of specific staining techniques, especially immunohistochemistry, cellular biochemistry and structure have been related to the specific hormonal secretions of these cells. With routine staining there is a separation of three distinctive cell populations: endocrinocytus acidophilus, endocrinocytus basophilus, and endocrinocytus chromophobus. The frequency of occurrence of each cell type varies according to the age, sex, breed, and physiologic state. Francis and Mulligan (1949) reported that in the adult male dog the acidophilic cells outnumbered the basophilic cells approximately five to one and that the chromophobic cells occurred with three times the frequency of the basophilic cells. Stockard (1941) reported that the basophilic cells were outnumbered 30 to 1 by the acidophilic cells. White and Foust (1944) reported no significant sex differences and a ratio of 11 to 1, acidophilic to basophilic cells.

The acidophilic endocrine cells have an affinity for acidic dyes, staining well with the acid dyes of the bichromic and trichromic procedures. The dye is taken up by the granules of the cytoplasm, which are stored secretory products. These cells are smaller than the basophilic cells, measuring approximately 15 µm in diameter. The acidophilic cells are located adjacent to sinusoids, in most cases being displaced only by basophilic cells from that site. Their distribution within the pars distalis adenohypophysis is generally uniform, with only a slight increase in their numbers near the inner aspect. During pregnancy the proportion of acidophilic cells increases and remains elevated, constituting approximately 65% of cells, until the end of lactation, when their numbers return to prepregnancy levels. These cells are of two types, one that produces a somatotrophin protein and another that produces a lactotrophin protein.

The basophilic endocrine cells possess cytoplasmic granules that have a moderate affinity for the basic component of routine laboratory stains. The granules are composed of glycoprotein and react positively when stained with dyes specific for that component. The cells are larger than the acidophilic cells, measuring approximately 20 µm in diameter, and are more elongated. Like the acidophilic cells, these cells are generally observed along a sinusoid. They occur in greater numbers at the periphery of the pars distalis adenohypophysis. Stockard (1941) has reported that basophilic cells proliferate during proestrus. Thyrotrophin and the gonadotrophins are the hormones produced by specific basophilic cell types.

The chromophobic cells do not stain well with routine dyes. They occur in moderate numbers near the central region of a racemose. Their nuclei are easily visible, but their cytoplasmic boundaries are difficult to determine. There is equivocal evidence that some of these cells, which lack marked staining affinity, produce adrenocorticotrophin (Goldberg & Chaikoff, 1952; Mikami, 1956; Purves, 1966). Ricci and Russolo (1973) present immunocytologic evidence that suggests this hormone is produced by the chromophils.

Many investigators have described a fourth cell type in the dog. Most believe it to be a functional variant (Hartman et al., 1946; Purves & Griesback, 1957; Smith et al., 1953; Wolf & Cleveland, 1932). Kagayama (1965) and Gale (1972) term this cell a stellate, or follicular cell. Goldberg and Chaikoff (1952), Carlon (1967), and Gale (1972) describe six cell types based on specific histochemistry or structural features.

The pars tuberalis adenohypophysis is composed of epithelioid cells packed between sinusoids in anastomosing walls or muralia. Occasionally, small follicles are seen. The cells are uniform in size, being low columnar, and in staining characteristics, being largely chromophobic. There are often a few cells typical of the chromophobic cells of the pars distalis adenohypophysis mixed among cells of the pars tuberalis adenohypophysis near that segment. Their cytoplasm is finely granular and reacts slightly positive with dyes for glycogen. When follicles occur, they are filled with a homogeneous glycoprotein and lined by a simple columnar epithelium. The tissues are also continuous with those of the pars intermedia adenohypophysis, with which it shares many structural and cytochemical features.

The parenchyma of the pars intermedia adenohypophysis is a complexly folded pseudostratified columnar epithelium. It envelops nearly all of the neural lobe of the neurohypophysis and is separated from it by only a delicate band of vascularized, pial connective tissue. The remnant of the vesicular space, the hypophyseal cavity, separates it from the pars distalis adenohypophysis. The pars intermedia adenohypophysis blends with the pars distalis adenohypophysis as it reflects distally to join with that part. Where it is continuous with the pars tuberalis adenohypophysis, the folded epithelium projects into the lumen of the hypophyseal cavity. These folds are more prominent in the brachycephalic breeds. Infrequently, there are villuslike projections extending for short distances into the neurohypophyseal tissues. The parenchyma is normally devoid of sinusoids but has access to numerous pial capillaries at the neurohypophyseal surface. Often these vessels can be seen projecting into the connective tissue septa of the folds. The epithelioid cells stain only faintly. Melanocyte-stimulating hormone and adrenocorticotropin are secreted by these cells (Halmi et al., 1981).

Cells of the neural lobe and the infundibulum are chiefly glial cells, which are termed gliocyti centrales (pituicytes). These cells support axons in an extensive neuropil. These axons are processes of neuronal cell bodies found in the nuclei of the hypothalamus and compose the supraopticohypophyseal and paraventriculohypophyseal tracts (Fig. 10-1). From these processes are released neurohumors produced in the hypothalamus and termed vasopressin and oxytocin. These neurohumors enter the systemic circulation. The tuberohypophyseal tracts convey releasing factors from numerous hypothalamic nuclei to the tuber cinereum and infundibulum where they enter the capillary loops that circulate to the adenohypophysis.

Vascularization

The blood supply and venous drainage of all the hypophyseal regions are structurally interrelated. The functional interdependence of the hypophyseal subdivisions is facilitated by their common vascularization.

The arterial supply of the hypophysis arises from two major sources, the internal carotid arteries and the caudal communicating arteries (Fig. 10-3). Several branches passing directly to the region of the gland arise from the rostral and caudal intercarotid arteries and the caudal communicating arteries. The number of vessels from these sources that converge on the hypophysis is extensive and was described by Dandy and Goetsch (1910) as appearing “like spokes to the hub of a wheel.” The rostral intercarotid artery provides a variable number of branches, 4 to 10, to the region of the infundibulum (Basir, 1932). An equally extensive group of vessels arises from the rostral communicating arteries. In addition, a vessel arises from each of the internal carotids and proceeds toward the infundibulum. Less prominent vessels may also originate from the caudal aspect of the arterial circle. All of these vessels pass centripetally toward the infundibulum where they join in forming a plexus, the mantle plexus (Green, 1951). The plexus is incorporated into the meningeal investment of the hypophysis.

From this mantle plexus many arterioles enter the tuber cinereum and provide capillaries to the primary blood capillary network (rete hemocapillare primarium). On the rostral and lateral surfaces of the tuber cinereum major vessels arise from the mantle plexus or as direct branches of the intercarotid vessels that are termed the rostral hypophyseal arteries. Several of these also provide capillaries to the tuber cinereum and the initial portion of the infundibulum and join in the primary blood capillary network (Akmayev, 1971a). These capillaries receive neurohumoral secretions called releasing factors, which are subsequently carried from this region of the hypothalamus, called the median eminence gland by Reichlin (1974), to the hypophysis via a portal blood vascular system (Campbell, 1970; Green, 1966). Akmayev (1971b) reported that those nuclei of the tuber cinereum that have the greatest vascularity have the smallest caliber capillaries. A major portion of the venous drainage from this capillary network returns to the surface of the infundibulum and is collected by veins that run parallel to its outer surface. These veins supply the sinusoids of the adenohypophysis. The capillaries (sinusoids) of the adenohypophysis form the secondary blood capillary network (rete hemocapillare secundus). The veins that connect these two capillary networks are the hypophyseal portal vessels (venulae portis hypophysis), meaning the gateway vessels to the gland. This portal circulation in the dog is less obvious than in some other species owing to the relatively short infundibulum in the dog. Green (1966) and Bergland and Page (1979) suggest a less direct influence of the circulation.

From the caudal rim of the mantle plexus a few arterioles pass directly to the neurohypophysis at its distal extremity. In this region the adenohypophysis does not completely invest the neural lobe. These arterioles, termed the caudal hypophyseal arteries, enter the parenchyma of the neural lobe and distribute as capillaries. A few small branches may pass to the pars distalis adenohypophysis.

The pars tuberalis adenohypophysis receives its blood supply from the hypophyseal portal vessels and the sinusoids of the pars distalis adenohypophysis; the latter also receives its supply from the portal vessels. The pars intermedia adenohypophysis lacks an intraepithelial vascular network. Instead, the epithelial cells rest on a basement membrane in close proximity to capillaries, the rete intermedius, in the stromal tissues coursing between the pars intermedia adenohypophysis and the neural lobe.

The neurohypophysis receives a blood vascular supply from the rostral hypophyseal arteries supplying the tuber cinereum and the infundibulum. The neural lobe also receives some small number of caudal hypophyseal arteries. Unlike in the adenohypophysis, within the neural tissue there are profiles of arterioles and some muscular arteries.

The regulation of the adenohypophysis by the hypothalamus is made possible by the architecture of the portal system. Structural and functional data suggest that blood entering the hypophysis from these multiple sources will eventually percolate through the sinusoids of the pars distalis adenohypophysis. From these sinusoids venous drainage is by way of vessels that exit from the gland parenchyma and empty into the cavernous and intercavernous sinuses (Dandy & Goetsch, 1910; Flerko, 1980; Green, 1951, 1966; Morato, 1939).

Innervation

The parenchyma of the neurohypophysis is primarily composed of axons that extend from cell bodies in the hypothalamic regions (Dandy, 1913; Watkins, 1975). The majority of these cell bodies are located in the supraoptic and paraventricular nuclei and, to a lesser degree, in other hypothalamic regions (Green, 1951). These axons extend into the neural lobe in the supraopticohypophyseal and paraventriculohypophyseal tracts. These are unmyelinated axons that convey and release a neurosecretory product. The nerve supply to the hypophysis passes primarily to the neurohypophysis Sympathetic axons arising from the cranial cervical ganglion pass by way of the tunica externa of the internal carotid artery and its branches to the vessels of the hypophysis (Dandy, 1913; Green, 1951; Truscott, 1944). A parasympathetic innervation has not been described. The results of ablation experiments suggest that hormonal output from the adenohypophysis is not under direct autonomic control. Yamada et al. (1956) and Green (1966) review the literature on innervation to portions of the adenohypophysis. Castel et al. (1984) provide a comprehensive review of neurosecretory systems and of the neurohypophyseal tracts specifically.

Macroscopic Features

Each gland is embedded in the deep cervical fascia and is closely adherent to the trachea (Fig. 10-4). The sternocephalicus muscle passes immediately lateral to the convex surface of each gland, and the sternothyroideus covers each thyroid on its ventral surface.

The cranial pole of the right thyroid lobe lies at the level of the caudal border of the cricoid cartilage of the larynx. Caudally, it extends to the region of the fifth tracheal ring. It is bounded dorsolaterally by the carotid sheath containing the common carotid artery, the internal jugular vein, the tracheal duct, and the vagosympathetic trunk. Axons of the recurrent laryngeal nerve pass cranially in close association with the right thyroid lobe. The stroma of the thyroid is continuous with and tightly bound within the pretracheal lamina of the cervical fascia and blends with the fascia of the carotid sheath.

The left thyroid lobe is generally indistinguishable from its counterpart in size and shape. It does differ in positional relationships, being further caudal, extending from the third through the eighth tracheal rings. Its dorsolateral boundary is formed by the esophagus. The caudal laryngeal nerve passes dorsal to the gland, and the trachea provides its medial boundary. The components of the carotid sheath on the left side are displaced by the esophagus and therefore are not in contact with the gland.

Mesoscopic Features

The thyroid gland of the adult has an organization of tissues based primarily upon follicles. The stromal connective tissues are best developed at the dorsal aspect, where many of the main vessels enter and leave the gland. From this dorsal median mass of stroma extend the septa, which incompletely subdivide the gland into lobules. The larger parenchymal follicles can be resolved with only slight magnification.

In some dogs there is a narrow connection between the two lobes. When present, this bridge, isthmus glandularis, composed of glandular parenchyma, passes horizontally as a band on the ventral surface of the trachea to connect the caudoventral aspects of each lobe. Such an isthmus is more frequently observed in the brachycephalic breeds, but can also be found in individuals of most other breeds.

The thyroid glands are intimately related structurally to the parathyroid glands. Each thyroid normally is related to a pair of these endocrine glands. One parathyroid is usually found near the cranial dorsolateral margin of the gland, but the positional relationship of the thyroid and the cranial parathyroid varies. This parathyroid (glandula parathyroidea externa [III]) in some individuals is a satellite only; in others it is indented into the surface of the thyroid and enveloped by the thyroid fascia, and in others it is embedded within the thyroid parenchyma. The second parathyroid (glandula parathyroidea interna [IV]) is more often not “para” in position, but is embedded within the thyroid at a depth that is variable, generally in the caudal portion of the gland.

Developmental Anatomy

The parenchyma of the thyroid develops from structures of the pharyngeal endoderm. Beginning at the 4-mm stage, the midventral surface of the pharynx gives rise to a tissue thickening, the thyroid diverticulum (Godwin, 1936). Further growth in size occurs predominantly at the distal end of the diverticulum. Its connection to the pharynx narrows to become a stalk before separating completely. If a connection persists, it may appear as a duct, the thyroglossal duct, with functional glandular epithelium and numerous cysts along its course.

After separating from its attachment to the pharynx, the median thyroid diverticulum forms a bilobed mass connected by a broad isthmus, oriented transversely on the ventral aspect of the trachea. As the primordium shifts caudally with morphogenesis of the head and neck, it passes near the developing pharyngeal pouches. A ventral component of the fourth pharyngeal pouch epithelium fuses with the median thyroid mass (Boyd, 1964; Godwin, 1937a). These components continue their development as a single unit, and any subsequent recognition of the contributing components is impossible. The isthmus narrows and in many cases remains only as a fibrous band connecting the caudal aspect of each gland. The orientation of each gland eventually parallels the trachea. The stroma of the glands is developed from the surrounding mesoderm.

An outstanding feature of thyroid development in the dog is the frequent occurrence of accessory thyroid tissue (glandula thyroidea accessoria). Islets of the rapidly proliferating cells of the thyroid primordia separate from the main mass and become incorporated in the developing structures of the neck and thorax. Functional accessory thyroid tissue is frequently found along the trachea, at the thoracic inlet, within the mediastinum, and along the thoracic portion of the descending aorta. Swarts and Thompson (1911) reported accessory thyroid tissue in the pericardial sac of 24 of 30 dogs examined. Halsted (1896), French (1901), Godwin (1936), and Kameda (1972) reported on the occurrence of numerous accessory thyroid tissues in the dog, and Smithcors (1964) reported some accessory tissues in all embryos and nearly one-half of adults examined.

As the main mass of developing thyroid parenchyma extends first ventrocaudally and then laterally, it incorporates cells that in the adult will function to produce calcitonin (thyrocalcitonin). The origin of these cells has long been considered pharyngeal endoderm of the fourth pharyngeal pouch. These cell groups of the developing neck, ultimobranchial bodies, fuse with and become dispersed within the developing thyroid parenchyma (Godwin, 1937a). As thyroid development proceeds, these cells occupy positions satellite to and between thyroid follicles (Nonidez, 1932a, b) and differentiate to form the parafollicular endocrine cells (endocrinocyti parafolliculares) and the interfollicular endocrine cells (endocrinocyti interfolliculares), respectively. Evidence presented by Pearse and Polak (1971) suggests that the ultimobranchial bodies are invaded by cells of the neural crest prior to their migration into the developing thyroid. They suggest a neural crest rather than pharyngeal endoderm as the tissue of origin for the parafollicular and interfollicular cells. Some interfollicular tissue forms interfollicular islets (insulae interfolliculares), which are believed to be stem cells for the formation of new thyroid follicles.

The developing cords of the thyroid analogue, which are solid initially, branch and separate to form isolated groupings that differentiate into small follicles prior to birth.