THE HYPOPHYSIS

The hypophysis or pituitary gland is sometimes described as the master gland because it produces certain hormones that directly influence the activities of other endocrine glands. Its location as an appendage of the brain also points to its significance as the relay between the nervous and humoral mechanisms that jointly control certain functions.

The hypophysis is a dark ellipsoidal body measuring about 1 × 0.75 × 0.5 cm in the medium-sized dog. It is suspended below the hypothalamus by a narrow, fragile stalk and is received into a depression (hypophysial fossa or sella turcica) of the cranial floor that is defined by rostral and caudal crests of bone. A covering of dura directly invests the gland and also roofs the depression, extending from its margins to embrace and confine the hypophysial stalk from all sides; this arrangement (diaphragma sellae) makes it exceedingly difficult to remove the brain at autopsy with the hypophysis attached.

Certain features of topography have a clinical or experimental interest. A large venous channel (cavernous sinus) to each side of the hypophysis provides a longitudinal connection between the ophthalmic plexus (and thus the veins of the face) rostrally and the external jugular vein and vertebral venous plexus caudally (p. 313); transverse (intercavernous) sinuses rostral and caudal to the gland complete an encircling venous ring. The internal carotid artery (or the emissary vessel from the rete mirabile that replaces this in the cat, ruminants, and pig [p. 311]) runs through the cavernous sinus to join the arterial circle below the brain. The optic chiasm is directly rostral to the hypophysis (see Figure 8–22/21,24), and laterally, flanking the cavernous sinus, are the cranial nerves that supply the adnexa of the eye (the oculomotor, trochlear, ophthalmic, and abducent nerves). Pathological growth or a physiological increase in the size of the hypophysis, which occurs in pregnancy, may exert pressure on these structures, especially on the optic nerves. Specific features in topography affect both the manner of expansion and the most convenient surgical approach. This is made via the nose and the sphenoidal sinus (within the cranial base, rostroventral to the hypophysial fossa) in human patients but more directly from below, via mouth, pharynx, and sphenoid in the dog. A temporal approach has been used in the pig.

Although the hypophysis appears to be a solid unitary organ, it comprises parts with very different origins and functions and includes certain spaces. One part, the neurohypophysis (posterior lobe), is formed by a downgrowth of the hypothalamus; the stalk that persists as the connection with the brain includes an extension of the third ventricle. The other part, the adenohypophysis (anterior lobe), is formed by an epithelial outgrowth of the roof of the developing mouth. It contains a flattened vestigial space, the hypophysial cleft; the tissue caudal to the cleft is directly applied to the neurohypophysis and is distinguished as the pars intermedia (intermediate lobe). The topographical relationships of the three “lobes” show some interspecific differences, but these need concern few readers (Figure 6–2).

Figure 6–2 Median sections of the hypophysis of the horse (A), ox (B), pig (C), and dog (D). The rostral extremity of the gland is to the left. 1, Adenohypophysis; 2, intermediate part; 3, neurohypophysis; 4, hypophysial stalk; 5, recess of third ventricle.

The adenohypophysis produces several hormones commonly designated by acronyms: growth (somatotropic) hormone (STH); gonadotropic hormones—follicle-stimulating (FSH) and luteinizing (LH); adrenocorticotropic hormone (ACTH); thyroid-stimulating hormone (TSH); and prolactin. The intermediate part produces α-melanocyte-stimulating hormone (MSH). The production of all these is controlled by regulating, hypophysiotropic hormones and releasing or inhibitory factors such as gonadotropin-releasing hormone (GnRH), somatostatin (SS), growth hormone-releasing hormone (GRH), and corticotropin-releasing hormone (CRH), to name the most important. They are produced by neurosecretory cells in several hypothalamic nuclei, particularly the paraventricular nucleus, preoptic area, arcuate nucleus, and periventricular nucleus. These hormones are secreted from their axon terminals and are discharged into fenestrated capillaries within the median eminence (see Figure 8–66/6); these releasing and inhibitory hormones are conveyed to a sinusoidal network within the adenohypophysis (Figure 6–3).

Figure 6–3 Organization of the brain–pituitary–peripheral organ axis. TRH, thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone; DA, dopamine; PIF, prolactin-inhibiting factor; GnRH, gonadotropin-releasing hormone; SS, somatostatin; GRH, growth hormone-releasing hormone; ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; PRL, prolactin. 1, Adrenal cortex; 2, thyroid; 3, liver; 4, ovary; 5, testis; 6, mammary gland; 7, median eminence; 8, anterior lobe of pituitary; 9, intermediate lobe of pituitary; 10, neural lobe of pituitary.

The hormones stored and later released into the circulation by the neurohypophysis include certain peptides, oxytocin, and vasopressin. Oxytocin stimulates contraction of the smooth muscle of the uterus and the myoepithelial cells of the udder. Vasopressin stimulates vasoconstriction and promotes fluid reabsorption by the kidneys. These substances are produced by magnocellular neurosecretory neurons within the supraoptic and paraventricular nuclei of the hypothalamus and are conveyed along the axons for direct release via the neurohypophysial capillary bed into the main circulation.

The adenohypophysis and neurohypophysis are separately vascularized. The latter is supplied by small branches from the internal carotid artery (or substitute vessel) and the arterial circle (of Willis) of the brain. The former is supplied indirectly; rostral hypophysial arteries, also from the internal carotid, expend themselves within the floor of the hypothalamus whence the blood is conveyed through the stalk by a portal system of veins. The capillary network of the adenohypophysis subsequently drains into the cavernous sinus.

Certain regions of the brain, collectively known as the circumventricular organs (CVOs), are distinguished from other parts by their susceptibility to direct chemosensory stimulation by substances carried within the bloodstream. They owe this distinction to the fenestration of perfusing capillaries, which allows large molecules to exchange between the plasma and the extracellular milieu of the CVO, a possibility elsewhere excluded by the existence of the blood–brain barrier. The name given to the assembly emphasizes the proximity of the component regions to the system of ventricles within the brain, which suggests a role for the cerebrospinal fluid in the diffusion of the chemical messengers. The neurons within the different regions are of course able to communicate through synaptic connections in the usual way but also allow CVOs to use neurohormonal mechanisms to influence peripheral function. The CVOs comprise the subfornical organ, the pineal gland, the subcommissural organ, the area postrema, the posterior lobe of the pituitary, the median eminence, and the vascular organ of the lamina terminalis (see Figure 8–66). It is difficult, if not impossible, to assign specific functions to different regions, and it is perhaps sufficient to say that they are broadly concerned with homeostatic and autonomic function (feedback regulation) and with the provision of neuroendocrine mechanisms of peripheral effect dependent on the entry of substances, produced by neurons in certain circumventricular regions, into the fenestrated capillaries for diffusion within the general circulation.

THE EPIPHYSIS

The epiphysis or pineal gland, named from the fancied resemblance of the human structure to a pine cone, is a small, darkly pigmented outgrowth from the dorsal aspect of the brain at the caudal end of the roof of the third ventricle and directly before the rostral colliculi (see Figure 8–22/11). In certain species it is related to a large outpouching (epiphysial recess) of the pia-ependyma that roofs the ventricle. It is concealed between the cerebral hemispheres and cerebellum in the intact brain.

The epiphysis is solid but is not always homogeneous as foci of calcification (“brain sand”) often develop with advancing age. Its functions were long obscure. It produces melatonin, an indolamine derived from serotonin, which possesses an antigonadotropic circadian effect. The existence of this hormone was first postulated from the observation that tumors that destroy the secretory tissue are frequently associated with precocious puberty.

The driving endogenous circadian clock is located in the hypothalamic suprachiasmatic nucleus (SCN), and its rhythm controls the rhythm of melatonin secretion by the pineal gland by a polysynaptic pathway. The autonomic innervation of the pineal gland runs via the superior cervical ganglion. Melatonin is secreted as a sleeping hormone during the night and acts on many brain areas, including the SCN and the pituitary. The brain knows that it is day by the enhanced activity of the SCN and knows that it is night by the secretion of melatonin. The action of melatonin on the pars tuberalis is important for seasonal hormonal fluctuations. Fine-tuning of the biological clock in the SCN can be achieved by gradual changes in daylight, which regulate both long-term (seasonal) and short-term (diurnal) variation in gonadal activity.

THE THYROID GLAND

The thyroid gland lies on the trachea directly behind, and sometimes overlapping, the larynx. Its form varies greatly: in the dog and the cat the gland consists of separate masses that are occasionally connected by an isthmus (Figure 6–4, A); in the horse, paired lobes are widely dissociated but connected by an insubstantial isthmus (Figure 6–4, B); in cattle the lobes are connected by a wide isthmus of parenchymal tissue (Figure 6–4, C); in small ruminants the isthmus is inconstant and when present is a mere connective tissue strand. In yet other species the thyroid has a more compact form and exhibits a relatively large median (pyramidal) lobe in addition to the lateral lobes. This arrangement, found in pigs and human subjects, provides a cover on the trachea that extends toward the thoracic inlet (Figure 6–4, D); it explains the name given to the gland.*

Figure 6–4 The thyroid gland of the dog (A), horse (B), cattle (C), and pig (D). The inset to D illustrates the subtracheal connection in transverse section in the pig. 1, Isthmus; 2, trachea; 3, cricopharyngeus.

The gland has its origin in a median outgrowth from the part of the pharyngeal floor that contributes to the tongue (p. 142). The primordium extends caudally on the ventral surface of the trachea before dividing at its apex into divergent processes that extend dorsolaterally to reach the boundary between the trachea and the esophagus (Figure 6–5/2). In most mammals the connection with the developing tongue (thyroglossal duct) is never patent and it later regresses in its entirety.

Figure 6–5 The pharyngeal primordia of certain endocrine structures; dorsal view, schematic. 1, Thyroglossal duct; 2, thyroid gland; 3, first pharyngeal pouch; 3′, external acoustic meatus; 4, palatine tonsil (second pouch); 5, parathyroid III; 6, thymus; 7, parathyroid IV; 8, ultimobranchial body.

The mature gland is enclosed within a connective tissue capsule that is loosely attached to neighboring organs. Its substance, generally brick-red, obtains a rather granular texture from the many enclosed follicles of which it is composed. In some species (e.g., cattle) these give the intact organ an irregular appearance, but in others (e.g., dog) the surface is quite smooth. The tissue is relatively firm, and this consistency, allied to the form, size, and location, enables the lobes to be identified in larger species by palpation caudal to the larynx. They are not palpable in the healthy dog.

The size of the thyroid gland varies greatly, depending to a large extent on the iodine content of the diet; when this content is deficient, enlargement (goiter) may develop, and in some parts of the world it is customary to add iodine to table salt as a preventive measure. In dogs the relative weight of the thyroid may vary by a factor of as much as six, although the increasing use of commercial foods (of uniform composition) now tends to reduce this variation. Average dimensions in medium-sized dogs are of the order of 6 × 1.5 × 0.5 cm. Accessory masses of thyroid tissue are sometimes located along the cervical trachea and are occasionally carried into the thorax by the descending heart.

The gland is mainly supplied by the cranial thyroid artery, which arises from the common carotid artery and arches around the cranial pole. A subsidiary supply is occasionally provided by a caudal thyroid artery, which takes a more proximal origin. In the dog the two vessels are connected by a substantial anastomosis along the dorsal margin. The venous drainage is to the internal jugular vein. The glandular tissue receives both sympathetic and parasympathetic fibers; the former is routed through the cranial cervical ganglia, the latter through the laryngeal branches of the vagus nerves. The fibers are predominantly vasomotor, and denervation has little effect on secretory activity.

The main lymph drainage of the thyroid in the dog proceeds to the cranial deep cervical nodes.

The thyroid hormones, concerned with metabolism and growth, are produced by the follicular cells that compose the bulk of the parenchyma. They are stored in the follicular fluid and later broken down to yield the final products, which are released into the bloodstream.

A small portion of the parenchyma is provided by parafollicular (or C) cells. These appear to have their origin in the ultimobranchial bodies that derive from epithelial clusters of the fourth pharyngeal pouches that are invaded by neural crest cells (Figure 6–5/8). C cells produce calcitonin, a hormone antagonistic to parathormone in some species. It also seems to play a role in fetal bone growth, and it protects the maternal skeleton against excessive demineralization.

THE PARATHYROID GLANDS

Usually four parathyroid glands, small epithelial bodies located close to or embedded within the much larger thyroid, are present. The parathyroid glands also develop from the pharyngeal lining; one pair (parathyroids III or external parathyroid glands) comes from the third pharyngeal pouches, the other (parathyroids IV or internal parathyroid glands) from the fourth pouches (Figure 6–5/5,7). In the dog, cat, and small ruminants the parathyroid glands generally become recessed or embedded within the substance of the thyroid gland and frequently escape notice in routine dissections. Once exposed, they can be identified by their pale color, which contrasts with the thyroid tissue. In cattle and the horse they are usually located close to the thyroid gland.

The parathyroids III are carried down the neck by the developing thymus and come to rest at various levels, generally near the carotid bifurcations but much farther caudally in the horse (in which they may approach the thoracic inlet). They are also not always easily recognizable because they resemble small lymph nodes; however, they are paler and lack the smooth, glistening exterior of these. These glands are usually located at the rostral end of the thyroid gland in the dog and at the caudal end in the cat.

The parathyroid hormone (parathormone) plays a vital role in the regulation of various aspects of calcium metabolism: absorption from the gut, mobilization from the skeleton, and excretion in the urine. The production of the hormone is largely regulated by the calcium plasma concentration. The close relationship of the parathyroid glands to the thyroid points to the need for caution in thyroid surgery.

THE ADRENAL GLANDS

The paired adrenal glands lie against the roof of the abdomen near the thoracolumbar junction. They are retroperitoneal and usually located craniomedial to the corresponding kidney (more directly medial in the horse). Although they obtain their name from this relationship, they are in fact more closely connected with the major vessels in the abdomen—the aorta on the left, caudal vena cava on the right—and they adhere to these when the kidneys shift from the accustomed positions (e.g., the left kidney of the ruminant; see p. 693).

Although generally elongated, the glands are often asymmetrical and quite irregular, being molded on neighboring vessels (Figure 6–6/1). It is difficult to specify their size because this appears to be influenced by several factors; they are relatively larger in wild than in related domestic forms, in juvenile than in adult individuals, and in pregnant and lactating females than in those reproductively inactive. Those of a medium-sized dog commonly measure about 2.5 × 1 × 0.5 cm.

Figure 6–6 The topography of the canine adrenal glands. 1, 1′, Right and left adrenal glands; 2, left kidney; 3, aorta; 4, caudal vena cava; 5, phrenicoabdominal vessels; 6, renal vessels; 7, ovarian vein; 8, ureter; 9, bladder.

Adrenal glands are firm, solid bodies that fracture readily when flexed. The fractured (or sectioned) surface exposes the division of the interior into an outer cortex and an inner medulla. The cortex, covered by a fibrous capsule, is yellowish and radially striated; the much darker medulla has a more uniform appearance. The two parts also contrast in origin, in microscopic structure, and in function.

The cortex is mesodermal and derived from a patch of celomic epithelium close to the gonadal fold. On gross inspection, certain color changes vaguely suggest a subdivision into several concentric shells (zones), but these distinctions become clear only in microscopic preparations. The outer zone produces the mineralocorticoid hormone. The subjacent zones produce glucocorticoids and certain sex steroids.

The medulla is of ectodermal origin, being contributed by a parcel of the cells that migrates from the neural crest to provide the neurons of the peripheral sympathetic ganglia. The medullary cells produce the transmitter substances norepinephrine and epinephrine and thus share with the sympathetic nervous system in the control of the body’s response (“flight or fight”) to acute stress situations. These cells obtain the additional designation chromaffin from their marked affinity for the salts of chromium and other heavy metals.

The adrenal glands are variously but always generously vascularized by small branches from several neighboring trunks: the aorta and the renal, lumbar, phrenicoabdominal, and cranial mesenteric arteries. After perfusing the gland, the blood pools within a central vein from which emissary vessels lead through a hilus to join the caudal vena cava or a tributary. Though not easily found, fine nerves within the cortex subject the tissue to hypothalamic control. Nerve bundles are more readily demonstrated within the medulla; appropriately, these are predominantly sympathetic preganglionic fibers passing to the medullary cells, which are equivalent to sympathetic postganglionic neurons elsewhere.

Accessory masses of cortical and medullary tissue both occur. Those of cortical tissue may be incorporated within any of several organs but are most commonly found attached to the capsule of the adrenal gland itself. Accessory chromaffin cells form the bodies known as paraganglia, which are endocrine cell clusters particularly associated with sympathetic nerves; a prominent example is found within the plexus on the aorta, close to the origin of the cranial mesenteric artery. Similar clumps of nonchromaffin cells, usually assigned to the parasympathetic system, are best known from the carotid and aortic bodies (described in Chapter 7, p. 241).

OTHER ENDOCRINE TISSUES

The other endocrine tissues are incorporated within organs of composite function. The most familiar example is provided by the endocrine component of the pancreas, the pancreatic islets, also known as the islets of Langerhans. The general anatomy of the pancreas has already been described (p. 141). The endocrine component comprises many hundred (or thousand) islets of varying size unevenly distributed among the predominant exocrine tissue. The islets are not normally visible to the naked eye, but the larger ones—of pinhead size—can be made apparent by the use of intravital dyes. The islet tissue has the same origin as the exocrine pancreas and buds from the epithelial cords at an early stage; it remains solid when the remainder of the “tree” canalizes.

The islet cells are of several types (the exact number is disputed); the two most numerous are the alpha and beta types, which produce glucagon and insulin, respectively. These hormones affect carbohydrate metabolism, and their role is best known from the diabetes that develops when insufficient insulin is produced by the islet tissue. The pancreas is also the source of certain other hormones, including somatostatin and pancreatic polypeptide. Other less numerous cells manufacture gastrin; the distinction and functions of yet other types are in dispute. The relative frequencies of the different types are not the same in all parts of the pancreas, and some evidence exists that different ratios occur in the parts that originate from the dorsal and ventral primordia.

The endocrine components and functions of the testes (p. 186), ovaries (p. 205), and placenta (p. 211) were sufficiently mentioned in Chapter 5.

The endocrine components of other organs are even more discrete and thus are not described as they make no gross representation. The most important examples are the renin-producing juxtaglomerular complexes within the kidney and the variety of enteroendocrine cells scattered within the gastric and intestinal epithelia (p. 131). The number, distinctions, and functions of the enteroendocrine cell types are inadequately known. Although mainly scattered singly, these cells are so numerous that they would constitute a considerable gland if massed together. They are considered to belong to the so-called APUD* cell system (now shown to be of endodermal not neuroectodermal origin, as formerly supposed) and are believed to produce gastrin, secretin, glucagon, vasoactive intestinal peptide, gastric inhibitory peptide, and several other hormones.