Histology_Ross

Histology_Ross. Lymphatic vessels have also been demonstrated in the parenchyma of the adrenal medulla. Recent physiologic studies indicate an important role of the lymph vessels in distributing high-molecular-weight secretory products of chromaffin cells, such as chromogranin A, into the circulation. Cells of the Adrenal Medulla Chromaffin cells located in the adrenal medulla are innervated by presynaptic sympathetic neurons.


Histology_Ross

Histology_Ross. The central portion of the adrenal gland, the medulla, is composed of a parenchyma of large, pale-staining epithelioid cells called chromaffn cells (medullary cells), connective tissue, numerous sinusoidal blood capillaries, and nerves. The chromaffin cells are, in effect, modified neurons (Folder 21.5). Numerous myelinated, presynaptic sympathetic nerve fibers pass directly to the chromaffin cells of the medulla (see Chapter 12, page 378). When nerve impulses carried by the sympathetic fibers reach the catecholamine-secreting chromaffin cells, they release their secretory products. Therefore, chromaffin cells are considered the equivalent of postsynaptic neurons. However, they lack axonal processes. Experimental studies reveal that when chromaffin cells are grown in culture, they extend axon-like processes. However, axonal growth can be inhibited by glucocorticoids— hormones secreted by the adrenal cortex. Thus, the hormones of the adrenal cortex exert control over the morphology of


Histology_Ross

Histology_Ross. axon-like processes. However, axonal growth can be inhibited by glucocorticoids— hormones secreted by the adrenal cortex. Thus, the hormones of the adrenal cortex exert control over the morphology of the chromaffin cells and prevent them from forming neural processes. Chromaffin cells therefore more closely resemble typical endocrine cells, in that their secretory product enters the bloodstream via the fenestrated capillaries.


Histology_Ross

Histology_Ross. Ganglion cells are also present in the medulla. Their axons extend peripherally to the parenchyma of the adrenal cortex to modulate its secretory activity and innervate blood vessels, and extend outside the gland to the splanchnic nerves innervating abdominal organs. FIGURE 21.20 • Diagram illustrating the blood supply to the human adrenal gland. The region of the capsule, the zones within the cortex, and the medulla are indicated. (Modified from Warwick R, Williams PL, eds. Gray’s Anatomy, 35th ed. Edinburgh: Churchill Livingstone, 1973.) Chromaffin cells of the adrenal medulla have a secretory function. Chromaffn cells are organized in ovoid clusters and short interconnecting cords. The blood capillaries are arranged in intimate relation to the parenchyma. They originate either from the cortical capillaries or, as branches, from the cortical arterioles.


Histology_Ross

Histology_Ross. Ultrastructurally, the chromaffin cells are characterized by numerous secretory vesicles with diameters of 100 to 300 nm, profiles of rER, and a well-developed Golgi apparatus. The secretory material in the vesicles can be stained specifically to demonstrate histochemically that the catecholamines epinephrine and norepinephrine secreted by the chromaffin cells are produced by different cell types (Fig. 21.22). The TEM also reveals two populations of chromaffin cells distinguished by the nature of their membrane-bounded vesicles:  One population of cells contains only large dense core vesicles. These cells secrete norepinephrine.  The other population of cells contains vesicles that are smaller, more homogeneous, and less dense. These cells secrete epinephrine. Exocytosis of the secretory vesicles is triggered by release of acetylcholine from presynaptic sympathetic axons that synapse with each chromaffin cell. secretes: secretes: secretes: secretes:


Histology_Ross

Histology_Ross. Exocytosis of the secretory vesicles is triggered by release of acetylcholine from presynaptic sympathetic axons that synapse with each chromaffin cell. secretes: secretes: secretes: secretes: FIGURE 21.21 • Diagram illustrating the organization of the cells within the adrenal gland and their relationship to the blood vessels. Refer to Figure 21.20 for identification of the blood vessels. The ultrastructural features of the basic cell types and their secretions are noted. (Modified from Warwick R, Williams PL, eds. Gray’s Anatomy, 35th ed. Edinburgh: Churchill Livingstone, 1973.)


Histology_Ross

Histology_Ross. Epinephrine and norepinephrine account for less than 20% of the contents of the medullary secretory vesicles. The vesicles also contain large amounts of soluble 48-kilodalton proteins, called chromogranins, that appear to impart the density to the vesicle contents. These proteins, along with ATP and Ca2 , may help to bind the low-molecular-weight catecholamines and are released with the hormones during exocytosis. The catecholamines, synthesized in the cytosol, are transported into the vesicles through the action of a magnesium-activated ATPase in the membrane of the vesicle. Drugs such as reserpine, which cause depletion of catecholamines from the vesicles, may act by inhibiting this transport mechanism. Glucocorticoids secreted in the cortex induce the conversion of norepinephrine to epinephrine in chromaffin cells.


Histology_Ross

Histology_Ross. Glucocorticoids secreted in the cortex induce the conversion of norepinephrine to epinephrine in chromaffin cells. Glucocorticoids produced in the adrenal cortex reach the medulla directly through the continuity of the cortical and medullary sinusoidal capillaries. They induce the enzyme that catalyzes the methylation of norepinephrine to produce epinephrine. The nature of the blood flow correlates with regional differences in distribution of norepinephrineand epinephrine-containing chromaffin cells. The epinephrine-containing cells are more numerous in areas of the medulla  FOLDER 21.5 Clinical Correlation: Chromaffin Cells and Pheochromocytoma


Histology_Ross

Histology_Ross. Chromaffn cells (so named because they react with cells that secrete norepinephrine in comparison with the chromate salts) of the adrenal medulla are part of the amine normal adrenal medulla that comprises about 85% precursor uptake and decarboxylation (APUD) system of epinephrine-secreting cells. Stimulation of -adrenergic re-cells. The chromaffin reaction is thought to involve oxidation ceptors results in elevated blood pressure, increased car-and polymerization of the catecholamines contained within diac contractility, glycogenolysis, gluconeogenesis, and the secretory vesicles of these cells. Classically, chromaffin intestinal relaxation. Stimulation of -adrenergic receptors cells have been defined as being derived from neuroecto-results in an increase in heart rate and contractility. Surgiderm, innervated by presynaptic sympathetic nerve fibers, cal resection of the tumor is the treatment of choice. Care-and capable of synthesizing and secreting catecholamines. ful monitoring


Histology_Ross

Histology_Ross. Surgiderm, innervated by presynaptic sympathetic nerve fibers, cal resection of the tumor is the treatment of choice. Care-and capable of synthesizing and secreting catecholamines. ful monitoring with and -blockers is required during


Histology_Ross

Histology_Ross. A rare tumor derived from chromaffin cells called surgery to prevent hypertensive crises. pheochromocytoma produces excessive amounts of To summarize, pheochromocytomas are often described catecholamines. Because chromaffin cells are also found according to the “rule of 10’s”: outside of the adrenal medulla in paravertebral and prever- 10% are extraadrenal (paragangliomas) and of those,tebral sympathetic ganglia and other locations, tumors may 10% reside outside the abdomen. arise from outside the adrenal gland. These extraadrenal  10% occurs in children. pheochromocytomas are called paragangliomas be 10% are multiple or bilateral. cause scattered groups of chromaffin cells located among or near the components of the autonomic nervous system  10% are not associated with hypertension. (ANS) are called paraganglia. Episodic symptoms may  10% are malignant. occur, related to the pharmacological effects of excessive  10% are familial.


Histology_Ross

Histology_Ross. occur, related to the pharmacological effects of excessive  10% are familial. catecholamine secretion. Therefore, pheochromocytomas  10% recur after surgical removal. may precipitate life-threatening hypertension, cardiac arrhythmias, anxiety, and fear of impending death. Most  10% are found incidentally during unrelated imaging pheochromocytomas contain predominantly chromaffin studies. supplied with blood that has passed through the cortical sinusoids and thus contains secreted glucocorticoids. In some species, the norepinephrine-containing cells are more numerous in those regions of the medulla supplied by capillaries derived from the cortical arterioles. The catecholamines, in concert with the glucocorticoids, prepare the body for the “fight-or-flight” response.


Histology_Ross

Histology_Ross. The catecholamines, in concert with the glucocorticoids, prepare the body for the “fight-or-flight” response. The sudden release of catecholamines establishes conditions for maximum use of energy and thus maximum physical effort. Both epinephrine and norepinephrine stimulate glycogenolysis (release glucose into the bloodstream) and mobilization of free fatty acids from adipose tissue. The release of catecholamines also causes an increase in blood pressure, dilation of the coronary blood vessels, vasodilation of vessels supplying skeletal muscle, vasoconstriction of vessels conveying blood to the skin and gut, an increase in heart rate and output, and an increase in the rate and depth of breathing. Zonation of the Adrenal Cortex


Histology_Ross

Histology_Ross. Zonation of the Adrenal Cortex The adrenal cortex is divided into three zones on the basis of the arrangement of its cells (Fig. 21.23):  Zona glomerulosa, the narrow outer zone that consti tutes up to 15% of the cortical volume  Zona fasciculata, the thick middle zone that constitutes nearly 80% of the cortical volume  Zona reticularis, the inner zone that constitutes only 5% to 7% of the cortical volume but is thicker than the glomerulosa because of its more central location


Histology_Ross

Histology_Ross. The cells of the zona glomerulosa are arranged in closely packed ovoid clusters and curved columns that are continuous with the cellular cords in the zona fasciculata. Cells of the zona glomerulosa are relatively small and columnar or pyramidal. Their spherical nuclei appear closely packed and stain densely. In humans, some areas of the cortex may lack a recognizable zona glomerulosa. A rich network of fenestrated sinusoidal capillaries surrounds each cell cluster. The cells have abundant smooth-surfaced endoplasmic reticulum (sER), multiple Golgi complexes, large mitochondria with shelf-like cristae, free ribosomes, and some rER. Lipid droplets are sparse. The zona glomerulosa secretes aldosterone, which functions in the control of blood pressure.


Histology_Ross

Histology_Ross. The zona glomerulosa secretes aldosterone, which functions in the control of blood pressure. The cells of the zona glomerulosa secrete mineralocorticoids, compounds that function in the regulation of sodium and potassium homeostasis and water balance. The principal secretion, aldosterone, acts on the distal tubules of the nephron in the kidney, the gastric mucosa, and the salivary and sweat glands to stimulate resorption of sodium at these sites, as well as to stimulate excretion of potassium by the kidney. FIGURE 21.22 • Electron micrograph of medullary cells. Two types of medullary cells are present. The norepinephrinesecreting cells (NE) are identified by their vesicles, which contain a very dense core. The epinephrine-secreting cells (E) possess vesicles with less intensely staining granules. 15,000. The renin–angiotensin–aldosterone system provides feedback control of the zona glomerulosa.


Histology_Ross

Histology_Ross. The renin–angiotensin–aldosterone system provides feedback control of the zona glomerulosa. The zona glomerulosa is under feedback control of the renin–angiotensin–aldosterone system. The juxtaglomerular cells in the kidney release renin in response to a decrease in blood pressure or a low blood sodium level. Circulating renin catalyzes the conversion of circulating angiotensinogen to angiotensin I, which in turn is converted by angiotensin-converting enzyme (ACE) in the lung to angiotensin II. Angiotensin II then stimulates the cells of the zona glomerulosa to secrete aldosterone. As the blood pressure, sodium concentration, and blood volume increase in response to aldosterone, the release of renin from the juxtaglomerular cells is inhibited. Drugs that inhibit ACE in the lung are effective in the treatment of chronic essential hypertension.


Histology_Ross

Histology_Ross. The cells of the zona fasciculata are large and polyhedral. They are arranged in long straight cords, one or two cells thick, that are separated by sinusoidal capillaries. The cells of the zona fasciculata have a lightly staining spherical nucleus. Binucleate cells are common in this zone. TEM studies reveal characteristics typical of steroid-secreting cells, i.e., a highly developed sER (more so than cells of the zona glomerulosa) and mitochondria with tubular cristae. They also have a well-developed Golgi apparatus and numerous profiles of rER that may give a slight basophilia to some parts of the cytoplasm (Fig. 21.24). In general, however, the cytoplasm is acidophilic and contains numerous lipid droplets, although it usually appears vacuolated in routine histologic sections because of the extraction of lipid during dehydration. The lipid droplets contain neutral fats, fatty acids, cholesterol, and phospholipids that are precursors for the steroid hormones secreted by these cells.


Histology_Ross

Histology_Ross. The principal secretion of the zona fasciculata is glucocorticoids that regulate glucose and fatty acid metabolism.


Histology_Ross

Histology_Ross. The zona fasciculata secretes glucocorticoids, so called because of their role in regulating gluconeogenesis (glucose synthesis) and glycogenesis (glycogen polymerization). One of the glucocorticoids secreted by the zona fasciculata, cortisol acts on many different cells and tissues to increase the metabolic availability of glucose and fatty acids, both of which are immediate sources of energy. Within this broad function, glucocorticoids may have different, even opposite effects in different tissues:  In the liver, glucocorticoids stimulate conversion of amino acids to glucose, stimulate the polymerization of glucose to glycogen, and promote the uptake of amino acids and fatty acids. In adipose tissue, glucocorticoids stimulate the break down of lipids to glycerol and free fatty acids. In other tissues, they reduce the rate of glucose use and promote the oxidation of fatty acids. In cells such as fibroblasts, they inhibit protein synthesis and even promote protein catabolism to


Histology_Ross

Histology_Ross. In other tissues, they reduce the rate of glucose use and promote the oxidation of fatty acids. In cells such as fibroblasts, they inhibit protein synthesis and even promote protein catabolism to provide amino acids for conversion to glucose in the liver.


Histology_Ross

Histology_Ross. Glucocorticoids also depress the immune and inﬂammatory responses and, as a result of the latter, inhibit wound healing. Hydrocortisone, a synthetic form of cortisol is used in treatment of allergies and inﬂammation. It depresses the inﬂammatory response by suppressing interleukin 1 (IL-1) and IL-2 production by lymphocytes and macrophages. Glucocorticoids also stimulate destruction of lymphocytes in lymph nodes and inhibit mitosis by transformed lymphoblasts. Cells of the zona fasciculata also secrete small amounts of gonadocorticoids, principally androgens. ACTH regulates secretion of the zona fasciculata.


Histology_Ross

Histology_Ross. ACTH regulates secretion of the zona fasciculata. The secretion and production of glucocorticoids and sex steroids by the zona fasciculata is under feedback control of the CRH–ACTH system. ACTH is necessary for cell growth and maintenance and also stimulates steroid synthesis and increases blood flow through the adrenal gland. Exogenous ACTH maintains the structure and function of the zona fasciculata after hypophysectomy. In animals, administration of ACTH causes hypertrophy of the zona fasciculata. Circulating glucocorticoids may act directly on the pituitary gland, but they most commonly exert their feedback


Histology_Ross

Histology_Ross. Circulating glucocorticoids may act directly on the pituitary gland, but they most commonly exert their feedback FIGURE 21.23 • Photomicrographs of the cortex and medulla of the human adrenal gland. a. This photomicrograph shows an H&E–stained specimen of the outer cortex. It includes the connective tissue capsule, the zona glomerulosa, and the zona fasciculata. Continuous with the zona glomerulosa are the straight cords of cells that characterize the zona fasciculata. Between the cords are the capillaries and the less numerous arterioles. The red linear stripes represent capillaries that are engorged with red blood cells. 120.


Histology_Ross

Histology_Ross. b. The deep parts of the zona fasciculata, zona reticularis, and medulla are shown here. Note that the linear arrays of the cords in the zona fasciculata give way to irregular groups of cells of the zona reticularis. The medulla, in contrast, consists of ovoid groups of cells and short interconnecting cords of cells. A central adrenomedullary vein is also seen here. Note the thick longitudinally sectioned smooth muscle in part of its wall. 120. control on neurons in the arcuate nucleus of the hypothalamus, causing the release of CRH into the hypothalamohypophyseal portal circulation. Evidence also suggests that circulating glucocorticoids and the physiologic effects that they produce stimulate higher brain centers that, in turn, cause the hypothalamic neurons to release CRH. The zona reticularis produces glucocorticoids and androgens.


Histology_Ross

Histology_Ross. The zona reticularis produces glucocorticoids and androgens. The cells of the zona reticularis are noticeably smaller than those of the zona fasciculata, and their nuclei are more deeply stained. They are arranged in anastomosing cords separated by fenestrated capillaries. The cells have relatively few lipid droplets. Both light and dark cells are seen. Dark cells have abundant large lipofuscin pigment granules, and deeply staining nuclei are evident. The cells in this zone are small because they have less cytoplasm than the cells in the zona fasciculata; thus the nuclei appear more closely packed. They exhibit features of steroid-secreting cells, namely, a well-developed sER and numerous elongated mitochondria with tubular cristae, but they have little rER. The principal secretions of the zona reticularis are weak androgens.


Histology_Ross

Histology_Ross. The principal secretions of the zona reticularis are weak androgens. The principal secretion of the cells in the zona reticularis consists of weak androgens, mostly dehydroepiandrosterone (DHEA). The cells also secrete some glucocorticoids, in much smaller amounts than those of the zona fasciculata. Here, too, the principal glucocorticoid secreted is cortisol. The zona reticularis is also regulated by the feedback control of the CRH–ACTH system and atrophies after hypophysectomy. Exogenous ACTH maintains the structure and function of the zona reticularis after hypophysectomy. The fetal adrenal gland consists of an outer narrow permanent cortex and an inner thick fetal cortex or fetal zone.


Histology_Ross

Histology_Ross. The fetal adrenal gland consists of an outer narrow permanent cortex and an inner thick fetal cortex or fetal zone. Once fully established, the fetal adrenal gland is unusual in terms of its organization and its large size relative to other developing organs. The gland arises from mesodermal cells located between the root of the mesentery and the developing gonad zone (see Fig. 21.19a). The mesodermal cells penetrate the underlying mesenchyme and give rise to a large


Histology_Ross

Histology_Ross. FIGURE 21.24 • Electron micrograph of cells in the zona fasciculata. The boundary between adjacent cells of the cord is indicated by the arrowheads. Lipid droplets (L) are numerous (the lipid has been partially extracted). 15,000. Inset. A higher magnification of an area in the cell at the top of the micrograph reveals the extensive sER that is characteristic of steroid-secreting cells. Portions of the Golgi apparatus are also evident. 40,000 eosinophilic cell mass that will become the functional fetal terms of body weight and is only slightly smaller than the cortex or zone (see Fig. 21.19b). Later, a second wave of adjacent kidney. At term, the adrenal glands are equivalent cells proliferates from the mesenchyme and surrounds the in size and weight to those of the adult and produce 100 to primary cell mass (see Fig. 21.19c). By the fourth fetal 200 mg of steroid compounds per day, about twice that of month, the adrenal gland reaches its maximum mass in the adult adrenals.


Histology_Ross

Histology_Ross.  FOLDER 21.6 Functional Considerations: Biosynthesis of Adrenal Hormones


Histology_Ross

Histology_Ross. Cholesterol is the basic precursor of several steroid hor-mones, namely, corticosteroids, sex hormones, bile acids, and vitamin D. About half of the cholesterol in the body comes from the diet and the other half derives from de novo biosynthesis. Cholesterol synthesis occurs in the cytoplasm and organelles from acetyl-CoA. Biosynthesis in the liver accounts for approximately 10%, and in the in-testines, approximately 15%, of the amount produced each day. In addition, a small portion of cholesterol is synthe-sized by the adrenal cortical cells. Both dietary cholesterol and that synthesized de novo are transported within low-density lipoproteins (LDLs). Cholesterol is stored in lipid droplets within the cytoplasm of adrenal cortical cells in the form of cholesterol esters. Steroid hormones in adrenal glands are synthesized from cholesterol esters by removal of part of the side chain and modifications at specific sites on the remainder of the molecule. The enzymes catalyzing these


Histology_Ross

Histology_Ross. in adrenal glands are synthesized from cholesterol esters by removal of part of the side chain and modifications at specific sites on the remainder of the molecule. The enzymes catalyzing these modifications are located in different zones of the cortex as well as in differ-ent cytoplasmic sites within the cells. For instance, cleav-age of the side chain is catalyzed by P450-linked side chain cleavage enzyme (P450ssc) or desmolase, which is found only in mitochondria of steroid-producing cells. The other enzymes necessary for steroid production are located within sER, cytosol, and mitochondria. Thus, a precursor molecule may move from the sER to a mitochon-drion and back again several times before the definitive molecular structure of a given corticosteroid is obtained. Cholesterol esters removed from cytoplasmic lipid droplets and used in steroid hormone synthesis are quickly replenished from the cholesterol esters contained within LDL carried in the bloodstream. These esters are the


Histology_Ross

Histology_Ross. removed from cytoplasmic lipid droplets and used in steroid hormone synthesis are quickly replenished from the cholesterol esters contained within LDL carried in the bloodstream. These esters are the pri-mary source of the cholesterol used in corticosteroid syn-thesis. Under conditions of short-term or prolonged ACTH stimulation, the lipid stores in adrenal cortical cells are re-cruited for corticosteroid synthesis.


Histology_Ross

Histology_Ross. FIGURE 21.25 • Photomicrographs of a human fetal adrenal gland. a. Low-power micrograph of an H&E–strained section of a fetal adrenal gland. The permanent cortex (PC) is indicated in the upper portion of the micrograph. Below is the fetal zone (FZ ) in which the cells are arranged in anastomosing linear cords. Some of the capillaries (C) are engorged with red blood cells, thereby making them more apparent. 100. b. Higher-power micrograph of the same specimen showing the capsule (Cap) and the underlying permanent cortex. The cells are arranged in arched groups that extend into short cords. Note the close proximity of the nuclei and the small amount of cytoplasm in these cells. 200. c. This micrograph shows the cells of the fetal zone at the same magnification as in b. Note the slightly larger size of the nuclei and the considerable amount of cytoplasm in each of the fetal zone cells. Also note the eosinophilia of the cytoplasm, compared with the more basophilic cytoplasm of the cells


Histology_Ross

Histology_Ross. size of the nuclei and the considerable amount of cytoplasm in each of the fetal zone cells. Also note the eosinophilia of the cytoplasm, compared with the more basophilic cytoplasm of the cells of the permanent cortex. 200. (Original specimen courtesy of Dr. William H. Donnelly.)


Histology_Ross

Histology_Ross. The histologic appearance of the fetal adrenal gland is superficially similar to that of the adult adrenal gland. During late fetal life, most of the gland consists of cords of large eosinophilic cells that constitute approximately 80% of its mass. This portion of the gland, referred to as the fetal cortex (also called fetal zone), arises from the initial mesodermal cell migration. The remainder of the gland is composed of the peripheral layer of small cells with scanty cytoplasm. This portion, referred to as the permanent cortex, arises from the secondary mesodermal cell migration. The narrow permanent cortex, when fully established in the embryo, appears similar to the adult zona glomerulosa. The cells are arranged in arched groups that extend into short cords. They, in turn, become continuous with the cords of the underlying fetal zone (Fig. 21.25). In H&E preparations, the cytoplasm of the cells in the permanent cortex exhibits some basophilia; in combination with the closely


Histology_Ross

Histology_Ross. continuous with the cords of the underlying fetal zone (Fig. 21.25). In H&E preparations, the cytoplasm of the cells in the permanent cortex exhibits some basophilia; in combination with the closely packed nuclei, this gives this part of the gland a blue appearance, in contrast to the eosinophilic staining of the fetal zone.


Histology_Ross

Histology_Ross. With the TEM, the cells of the permanent cortex exhibit small mitochondria with shelf-like cristae, abundant ribosomes, and small Golgi profiles. The cells of the fetal zone, in contrast, are considerably larger and are arranged in irregular cords of varying width. With the TEM, these cells exhibit spherical mitochondria with tubular cristae, small lipid droplets, an extensive sER that accounts for the eosinophilia of the cytoplasm, and multiple Golgi profiles. Collectively, these features are characteristic of steroid-secreting cells. The development of the fetal adrenal gland is a part of a complex process of maturation and preparation of the fetus for extrauterine life.


Histology_Ross

Histology_Ross. The development of the fetal adrenal gland is a part of a complex process of maturation and preparation of the fetus for extrauterine life. The fetal adrenal lacks a definitive medulla. Chromaffin cells are present but are scattered among the cells of the fetal zone and are difficult to recognize in H&E preparations. The chromaffin cells originate from the neural crest (see Fig. 21.19a) and invade the fetal zone at the time of its formation (see Fig. 21.19b). They remain in this location in small, scattered cell clusters during fetal life (see Fig. 21.19c). The blood supply to both the permanent cortex and the fetal zone is through sinusoidal capillaries that course between the cords and join to form larger venous channels in the center of the gland. Unlike the postnatal adrenal, arterioles are absent in the parenchyma of the fetal adrenal gland.


Histology_Ross

Histology_Ross. Functionally, the fetal adrenal gland is under the control of the CRH–ACTH feedback system through the fetal pituitary. It interacts with the placenta to function as a steroid-secreting organ because it lacks certain enzymes necessary for steroid synthesis that are present in the placenta. Similarly, the placenta lacks certain enzymes necessary for steroid synthesis that are present in the fetal adrenal gland. Thus, the fetal adrenal gland is part of a fetal–placental unit. Precursor molecules are transported back and forth between the two organs to enable synthesis of glucocorticoids, aldosterone, androgens, and estrogens.


Histology_Ross

Histology_Ross. At birth, the fetal cortex undergoes a rapid involution that reduces the gland within the first postnatal month to about a quarter of its previous size. The permanent cortex grows and matures to form the characteristic zonation of the adult cortex. With the involution and disappearance of the fetal zone cells, the chromaffin cells aggregate to form the medulla. If the adrenal glands fail to develop properly, congenital adrenal hyperplasia may result.


Histology_Ross

Histology_Ross. The pituitary gland is located in a bony fossa in the floor of the cranial cavity. It is connected by a stalk to the base of the brain. Although joined to the brain, only posterior lobe of the gland, the neurohypophysis, develops from the neural ectoderm. The larger anterior lobe of the pituitary, the adenohypophysis, develops from oral ectoderm as a diverticulum of the buccal epithelium, called Rathke’s pouch. The adenohypophysis regulates other endocrine glands. It is composed of clumps and cords of epithelioid cells, separated by large-diameter fenestrated capillaries. The neurohypophysis is a nerve tract whose terminals store and release secretory products synthesized by their cell bodies in the supraoptic and paraventricular nuclei. The secretions contain either oxytocin or vasopressin (antidiuretic hormone [ADH]). Other neurons from the hypothalamus release secretions into the fenestrated capillaries of the infundibulum, the first capillary bed of the hypophyseal portal system


Histology_Ross

Histology_Ross. (antidiuretic hormone [ADH]). Other neurons from the hypothalamus release secretions into the fenestrated capillaries of the infundibulum, the first capillary bed of the hypophyseal portal system that carries blood to the fenestrated capillaries of the adenohypophysis. These hypothalamic secretions regulate the activity of the adenohypophysis.


Histology_Ross

Histology_Ross. Pituitary, human, H&E ×50. This specimen is a sagittal section of the pituitary gland. The neurohypophysis, the posterior lobe of the gland, is delineated by the dashed line (indicated by arrows) that separates it from the adenohypophysis. The pars nervosa (PN ) is the expanded portion of the neurohypohysis that is continuous with the infundibulum. The pars tuberalis (PT ) of adenohypophysis is located around the infundibular stem but may cover the pars nervosa to a variable extent. The pars intermedia (PI ) is a narrow band of tissue that lies between Pars distalis, pituitary, human, H&E ×375. This photomicrograph shows a region of the pars distalis of adenohypophysis that is rich in acidophils (A). Basophils (B) are present in this area in lesser numbers. The acidophils are readily identified by the acidophilic staining of their cytoplasm, in contrast to the basophils whose cytoplasm is clearly Pars distalis, pituitary, human, H&E ×375.


Histology_Ross

Histology_Ross. Pars distalis, pituitary, human, H&E ×375. This photomicrograph shows a region of the pars distalis of adenohypophysis that is rich in basophils (B). At this particular site, there are no recognizable acidophils (at other sites, it is possible to find a more equal distribution of acidophils and Pars intermedia, pituitary, human, PAS/aniline blue-black ×80.


Histology_Ross

Histology_Ross. Pars intermedia, pituitary, human, PAS/aniline blue-black ×80. This photomicrograph shows a small portion of the pars distalis (PD); the remainder reveals the pars intermedia (Pl ) of adenohypophysis. The pars distalis shown here contains numerous capillaries filled with red blood cells, thus producing the pars distalis (PD) and the pars nervosa. It borders a small cleft (Cl ) that constitutes the remains of the lumen of Rathke’s pouch. The pars distalis, the anterior lobe of the gland, is its largest part. It contains a variety of cell types that are not uniformly distributed. This accounts for differences in staining (light and dark staining areas) that are seen throughout the pars distalis.


Histology_Ross

Histology_Ross. Each of the components of the adenohypophysis; i.e., the pars distalis, pars tuberalis, and pars intermedia, when examined at higher magnification, exhibit features at the cellular level that aid in their identification. These features are described in the following figures as well as those on Plate 81. basophilic. Chromophobes (C ) are also very numerous in this field. The cytoplasm stains poorly in contrast to that of the acidophils and basophils. The cells are arranged in cords and clumps, between which are capillaries (Cap), some of which can be recognized, but most are in a collapsed state and difficult to visualize at this magnification. basophils, though, typically, one cell type outnumbers the other in a given region). Chromophobes (C) are also relatively numerous at this site. In this particular region, the chromophobe nuclei are readily apparent, but the cytoplasm of the cells is difficult to discern.


Histology_Ross

Histology_Ross. the bright red appearance. The pars intermedia contains a number of small cysts (Cy). The cells that make up the pars intermedia, which is relatively small in humans, consist of small basophils and chromophobes. The basophils have taken up the blue stain, thus making them prominent. To the extreme right is a less cellular area, the pars nervosa (PN ). KEY A, acidophils B, basophils C, chromophobes Cap, capillaries Caps, capsule Cl, cleft Cy, cysts PD, pars distalis PI, pars intermedia PN, pars nervosa PT, pars tuberalis


Histology_Ross

Histology_Ross. The parenchyma of the pars distalis consists of two general cell types: chromophobes and chromophils. Chromophobes stain poorly; chromophils stain well. Chromophils are further subdivided into acidophils and basophils. Basophils stain with basic dyes or hematoxylin, whereas the cytoplasm of the acidophil stains with acid dyes such as eosin. The cytoplasm of basophils also stains with the periodic acid-Schiff (PAS) reaction because of the glycoprotein in its secretory granules. Acidophils can be further subdivided into two groups on the basis of special cytochemical and ultrastructural features. One group, called somatotropes, produces the growth hormone, somatotropic hormone (STH); the other group of acidophils, called lactotropes, produces the prolactin (PRL). The groups of basophils can also be distinguished with the electron microscope and with special cytochemical procedures. One group of thyrotropes produces the thyroid-stimulating hormone (TSH); another group of gonadotropes


Histology_Ross

Histology_Ross. also be distinguished with the electron microscope and with special cytochemical procedures. One group of thyrotropes produces the thyroid-stimulating hormone (TSH); another group of gonadotropes produces the gonadotropic hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH); and a third group of corticotropes produces adrenocorticotropic hormone (ACTH) and lipotropic hormone (LPH). Chromophobes are also a heterogeneous group of cells. Many are considered to be depleted acidophils or basophils.


Histology_Ross

Histology_Ross. Pars distalis, pituitary, human, Mallory ×360; inset ×1200. This photomicrograph of the pars distalis is from an area where there is an almost equal distribution of acidophils (A) and basophils (B). The clumps and cords of cells are delineated by strands of connective tissue (stained blue) that surround them. A number of engorged capillaries (Cap) containing red blood cells (stained yellow) are also seen. The acidophil cytoplasm in this preparation Pars nervosa, pituitary, human, H&E ×325.


Histology_Ross

Histology_Ross. Pars nervosa, pituitary, human, H&E ×325. The pars nervosa of neurohypophysis seen here contains cells called pituicytes, and unmyelinated nerve fibers form the supraoptic and paraventricular nuclei of the hypothalamus. The pituicytes (P) are comparable with neuroglial cells of the central nervous system. The nuclei are round to oval; the cyto plasm extends from the nuclear region of the cell as long processes. In H&E preparations such as this, the cytoplasm of the pituicyte cannot be stains a reddish or rust color. The basophils stain a reddish blue to deep blue, and the chromophobes (C ) exhibit a pale-blue color. The inset shows the three general cell types at higher magnification. The secretory granules of the acidophils (A) and basophils (B) are just discernable. It is the granules that stain and provide the overall coloration to the two cell types. In contrast, the chromophobe (C) lacks granules and simply reveals a pale-blue background color.


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Histology_Ross. distinguished from the unmyelinated nerve fibers. The hormones of the neurohypophysis, oxytocin and antidiuretic hormone (ADH) (also called vasopressin), are formed in the hypothalamic nuclei and pass via the fibers of the hypothalamohypophyseal tract to the neurohypophysis, where they are stored in the expanded nerve terminal portion of the nerve fibers. The stored neurosecretory material appears as Herring bodies (HB). In H&E preparations, the Herring bodies simply appear as small islands of eosinstained substance. Interspersed among the nerve fibers are capillaries (Cap). Pars nervosa, pituitary, human, PAS/aniline blue-black ×250; inset ×700.


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Histology_Ross. Pars nervosa, pituitary, human, PAS/aniline blue-black ×250; inset ×700. In this specimen from pars nervosa, the aniline blue has stained the nuclei of the pituicytes (P); the nerve fibers have taken up some of the stain to give a light-blue background. With this staining technique, the Herring bodies (HB) appear as the dark black islands. The inset shows the Herring body near the bottom of the micrograph at high magnification. The granular texture of the Herring body as seen here is a reflection of the accumulated secretory granules in the nerve terminals. Also of note in this specimen are the capillaries (Cap), which are prominent as a result of the contrasting red staining of the red blood cells within them. KEY A, acidophils B, basophils C, chromophobes Cap, capillaries HB, Herring bodies P, pituicytes


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Histology_Ross. The pineal gland (pineal body, epiphysis cerebri) is located in the brain above the superior colliculi. It de-velops from neuroectoderm but, in the adult, bears little resemblance to nerve tissue. Two cell types have been described within the pineal gland: parenchymal cells and glial cells. The full extent of these cells cannot be appreciated without the application of special methods. Those would show that the glial cells and the parenchymal cells have processes and that the processes of the parenchymal cells are expanded at their periphery. The parenchymal cells are more numerous. In an H&E preparation, the nuclei of the parenchymal cells are pale staining. The nuclei of the glial cells, on the other hand, are smaller and stain more intensely. Although the physiology of the pineal gland is not well understood, the secretions of the gland evidently have an antigonadal effect. For example, hypogenitalism has been reported in pineal tumors that consist chiefly of parenchymal cells,


Histology_Ross

Histology_Ross. is not well understood, the secretions of the gland evidently have an antigonadal effect. For example, hypogenitalism has been reported in pineal tumors that consist chiefly of parenchymal cells, whereas sexual precocity is associated with glial cell tumors (presumably, the parenchymal cells have been destroyed). In addition, experiments with animals indicate that the pineal gland has a neuroendocrine function whereby the pineal gland serves as an intermediary that relates endocrine function (particularly gonadal function) to cycles of light and dark. The external photic stimuli reach the pineal gland via optical pathways that connect with the superior cervical ganglion. In turn, the superior cervical ganglion sends postganglionic nerve fibers to the pineal gland. The extent to which these findings with laboratory animals apply to humans is not yet clear. Recent studies in humans suggest that the pineal gland has a role in adjusting to sudden changes in day length, such as those


Histology_Ross

Histology_Ross. these findings with laboratory animals apply to humans is not yet clear. Recent studies in humans suggest that the pineal gland has a role in adjusting to sudden changes in day length, such as those experienced by travelers who suffer from jet lag, and a role in regulating emo-tional responses to reduced day length during winter in temperate and subarctic zones (seasonal affec-tive disorder [SAD]).PI N EAL G LAN D 776


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Histology_Ross. Pineal gland, human, H&E ×180. The pineal gland is surrounded by a very thin capsule (Cap) that is formed by the pia mater. Connective tissue trabeculae (CT ) extend from the capsule into the substance of the gland dividing it into lobules. The lobules (L) appear often as indistinct groups of cells of varying size surrounded Pineal gland, human, H&E ×360; inset ×700.


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Histology_Ross. This micrograph shows at higher magnification the parenchyma of the pineal gland as well as a component called brain sand (BS) or corpora arenacea. When viewed at even higher magnifications, the corpora arenacea are seen to have an indistinct lamellated structure. Typically, they stain heavily with hematoxylin. The presence of these structures is an identifying feature of the pineal gland. A careful examination of the cells within the gland at the light microscopic level reveals two specific cell types. One cell type represents the parenchymal cells. These are by far the most numerous and are referred to as by the connective tissue. Blood vessels, generally small arteries (A) and veins (V ), course through the connective tissue. The arteries give rise to capillaries that surround and penetrate the lobules to supply the parenchyma of the gland. In this specimen and even at this low magnification, the capillaries (C ) are prominent as a consequence of the red blood cells present in


Histology_Ross

Histology_Ross. penetrate the lobules to supply the parenchyma of the gland. In this specimen and even at this low magnification, the capillaries (C ) are prominent as a consequence of the red blood cells present in their lumina.


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Histology_Ross. pinealocytes (or chief cells of the pineal gland). Pinealocytes are modified neurons. Their nuclei are spherical and are relatively lightly stained because of the amount of euchromatin that they contain. The second cell type is the interstitial cell or glial cell that constitutes a relatively small percentage of the cells in the gland. Their nuclei are smaller and more elongate than those of the pinealocytes. The inset reveals several glial cells (G) that can be identified by their more densely staining nuclei. The majority of the nuclei of the other cells seen here belong to pinealocytes. Also seen in the inset are several fibroblasts (F) that are present within a trabecula. KEY A, artery BS, brain sand C, capillary Cap, capsule CT, connective tissue F, fibroblast G, glial cell L, lobule V, vein


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Histology_Ross. The parathyroid glands are usually four in number. Each is surrounded by a capsule and lies on or is partially embedded in the thyroid gland. Connective tissue trabeculae extend from the capsule into the substance of the gland. The parathyroid glands elaborate a hormone that influences calcium and bone metabolism. Injection of parathyroid hormone into laboratory animals results in the release of calcium from bone by the action of osteocytes (osteocytic osteolysis) and osteoclasts. Removal of parathyroid glands results in a rapid drop in blood calcium levels. The thyroid gland is located in the neck in close relation to the upper part of the trachea and the lower part of the larynx. It consists of two lateral lobes that are joined by a narrow isthmus. The follicle, which consists of a single layer of cuboidal or low columnar epithelium surround-ing a colloid-filled space, is the functional unit of the thyroid gland. A rich capillary network is present in the connective tissue that


Histology_Ross

Histology_Ross. single layer of cuboidal or low columnar epithelium surround-ing a colloid-filled space, is the functional unit of the thyroid gland. A rich capillary network is present in the connective tissue that separates the follicles. The connective tissue also contains lymphatic capillaries.


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Histology_Ross. Parathyroid gland, human, H&E ×320. As seen here, the larger blood vessels are associated with the trabeculae (BV) and, occasionally, adipose cells (A). The parenchyma of the parathyroid glands appears as cords or sheets of cells separated by capillaries and delicate connective tissue septa.


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Histology_Ross. Two parenchymal cell types can be distinguished in routine H&E sections: chief cells (principal cells) and oxyphil cells. The chief cells (CC ) are more numerous. They contain a spherical nucleus surrounded by a small amount of cytoplasm. Oxyphil cells (OC ) are less numerous. They are conspicuously larger than chief cells but have a slightly smaller and more intensely staining nucleus. Their cytoplasm stains with eosin, and the boundaries between the cells are usually well marked. Moreover, the oxyphils are arranged in groups of variable size that appear scattered about in a much larger field of chief cells. Even with low magnification it is often possible to identify clusters of oxyphil cells because a unit area contains fewer nuclei than a comparable unit area of chief cells, as is clearly evident in this figure. Oxyphil cells appear during the end of the first decade of life and become more numerous around puberty. A further increase may be seen in older individuals.


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Histology_Ross. PARATHYROI D AN D THYROI D G LAN DS KEY A, adipose cells BV, blood vessels CC, chief cells CT, connective tissue F, follicles OC, oxyphil cells arrows, tangential section of follicle wall asterisks, shrinkage artifact Thyroid gland, human, H&E ×200. A histologic section of the thyroid gland is shown here. The thyroid follicles (F ) vary somewhat in size and shape and appear closely packed. The homogeneous mass in the center of each follicle is the colloid. The thyroid cells appear to form a ring around the colloid. Although the individual cells are difficult to distinguish at this magnification, the nuclei of the cells serve as an indication of their location and arrangement. Large groups of cells are seen in association with some follicles. Where the nuclei are of the same size and staining characteristics, one can conclude that in these sites, the section includes the wall of the follicle (arrows) in a tangential manner without including the lumen.


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Histology_Ross. There are two adrenal glands, one at the upper pole of each kidney. The gland is a composite of two distinct structural and functional components: a cortex and a medulla. The cortex develops from mesoderm and secretes steroid hormones; the medulla develops from neuroectoderm of the neural crest and secretes catecholamines. The adrenal cortex is divided into three zones according to the type and arrangement of its parenchymal cells. These are designated zona glomerulosa, zona fasciculata, and zona reticularis. The zona glomerulosa constitutes 15% of the cortical volume. It secretes mineralocorti-coids (aldosterone and deoxycorticosterone). The zona fasciculata constitutes nearly 80% of the cortical volume. It secretes the glucocorti-coids (cortisol, cortisone, and corticosterone) and a small amount of adrenal androgens. The zona reticularis (5% to 7% of cortical volume) produces most of the adrenal androgens. The zona fasciculata and the zona reticularis are regulated by


Histology_Ross

Histology_Ross. and a small amount of adrenal androgens. The zona reticularis (5% to 7% of cortical volume) produces most of the adrenal androgens. The zona fasciculata and the zona reticularis are regulated by adrenocorticotropic hormone (ACTH) secreted by the adenohypophysis in response to corticotropin-releasing factor (CRF) produced by the hypothalamus. The zona glomerulosa is not regulated by ACTH but is under feedback control of the renin-angiotensin-aldosterone system that also regulates blood pressure.


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Histology_Ross. Adrenal gland, human, H&E ×45. This low-magnification micrograph of a section through the partial thickness of an adrenal gland shows the outer capsule (Cap), the cortex (Cort) from one surface of the gland, the underlying medulla (Med ), and a very small portion of the cortex from the other surface of the gland (Cort, bottom center). The cortex has a distinctly different appearance in both structural organization Cortex, adrenal gland, human, H&E ×180. This is a higher magnification of a portion of the capsule and the full thickness of the cortex from an area in figure above. The capsule consists of dense connective tissue in which the larger arteries (A) travel to give rise to smaller vessels that will supply the cortex and medulla. The zona glomerulosa (ZG) is located at the outer part of the cortex, immediately under the capsule. The parenchyma of this zone consists of small cells that appear as arching cords or as oval groups of cells. Cortex, adrenal gland, human, H&E ×245.


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Histology_Ross. Cortex, adrenal gland, human, H&E ×245. This is a higher magnification of the area inscribed by the left rectangle in figure above. It shows the zona glomerulosa (ZG) and the outer portion of the zona fasciculata (ZF). Note the smaller size of the cells in the zona glomerulosa than those in the zona fasciculata. In addition, cells of the zona glomerulosa contain fewer lipid droplets than those of the zona fasciculata. and staining characteristics. From the inner portion, the medulla, note the lighter appearance of the medullary tissue. A small amount of adipose tissue (AT ) in which the gland is partially embedded is seen at the upper center of the micrograph. The corticomedullary boundary (dashed lines) has a wavelike contour, a reflection of the irregular shape of the gland. Within the medulla are a number of relatively large blood vessels (BV ). These are the adrenomedullary collecting veins that drain both the cortex and the medulla.


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Histology_Ross. The zona fasciculata (ZF ) consists of radially oriented cords and sheets of cells, usually two cells in width, that extend toward the medulla. The cells of the outer part of the zona fasciculata are generally larger than those of the inner portion of this zone and typically stain poorly because of the large number of lipid droplets that they contain. The cells of the zona reticularis (ZR) are relatively small and contain little or no lipid droplets and, consequently, stain prominently with eosin. Because of their small size, the nuclei are in close proximity to one another, much like the cells of the zona glomerulosa.


Histology_Ross

Histology_Ross. Typically, the cells in this part of the zona fasciculata are filled with lipid droplets, thus, the very poor staining characteristic of their cytoplasm. Delicate connective tissue trabeculae (arrows) extend from the capsule to surround the glomerular groups of cells and extend between the cords of cells in the zona fasciculata. Capillaries and arterioles are located within the connective tissue trabeculae. Usually, the capillaries are collapsed and, without the presence of red blood cells in their lumina, are thus difficult to identify.


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Histology_Ross. Cortex, adrenal gland, human, H&E ×245. in cords and contain lipid droplets, though in lesser amounts. The cells of This is a higher magnification of the area inscribed by the right the zona reticularis (ZR) are arranged in irregular anastomosing cords and rectangle in figure above. This deep portion of the zona fascic-contain at best only a small amount of lipid and, consequently, their cyto ulata (ZF) reveals smaller cells, although they are still arranged plasm stains with eosin. KEY A, arteries AT, adipose tissue BV, blood vessels Cap, capsule Cort, cortex Med, medulla ZF, zona fasciculata ZG, zona glomerulosa ZR, zona reticularis arrows, connective tissue trabeculae dashed line, corticomedullary boundary


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Histology_Ross. The cells of the adrenal medulla develop from the same source as the postganglionic cells of the sympathetic nervous system. They are directly innervated by preganglionic cells of the sympathetic system and may be regarded as modified postganglionic cells that are specialized to secrete. These cells produce the catecholamines epinephrine and norepinephrine. The adrenal medulla receives its blood supply via two routes: by arterioles that pass through the cortex and by capillaries that continue from the cortex, a type of portal circulation. Thus, some of the blood supplying the medulla contains cortical secretions that regulate medullary function. Blood leaves the medulla via the central adrenomedullary vein. Its structure is unusual in that the tunica media of the vessel contains prominent bundles of longitudinally oriented smooth muscle, the contraction of which facilitates rapid outflow of blood when medullary cate-cholamines are released.


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Histology_Ross. Medulla, adrenal gland, human, H&E ×175; inset ×250. This moderately low power photomicrograph shows the cells of the adrenal medulla. The medullary cells are organized in ovoid groups and short interconnecting cords. The cytoplasm of the medullary cells may stain with different intensity. The cytoplasm of some cells is very poorly stained, appearing almost clear, whereas others show greater intensity of eosin Central adenomedullary vein, adrenal gland, human, H&E ×350.


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Histology_Ross. Central adenomedullary vein, adrenal gland, human, H&E ×350. This higher-magnification view of the rectangle in the bottom left figure shows part of the lumen (L) of the central adrenomedullary vein (AMV) at the bottom of the field. The tunica intima (TI ) of the vessel is relatively thin but may con tain a variable amount of connective tissue. The smooth muscle (SM) of the staining. In this photomicrograph, a portion of the wall, namely, the tunica media (TM ) of the central adrenomedullary vein, can be seen. The nature of the central adrenomedullary vein is described in lower left figure. The inset shows the ovoid groups of medullary cells at a higher magnification. Between these groups of cells are capillaries (Cap) that, as in the cortex, can be identified when they contain red blood cells as shown here. Medulla, adrenal gland, human, H&E ×125.


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Histology_Ross. Medulla, adrenal gland, human, H&E ×125. This micrograph shows a central adrenomedullary vein (AMV ) that drains the adrenal medulla. The tunica media (TM) is unusually thick. The smooth muscle that constitutes this part of the vessel wall is in the form of bundles that are arranged longitudinally, that is, in the same direction as the vessel. Thus, the muscle seen here is cut in cross section, as is the vein. While the central adrenomedulary vein occupies most of the micrograph, medullary cells (MC) can be seen in several locations surrounding the vein. The portion of the figure outlined by the rectangle is seen at higher magnification in the bottom right figure.


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Histology_Ross. tunica media (TM) is readily seen here as being arranged in bundles and appears in cross section. There is no discrete tunica adventitia in this vein. Instead, its connective tissue blends in with surrounding structures. Ganglion cells (GC) are frequently found in proximity to the wall of the central adrenomedullary vein. They are large cells with a moderately basophilic cytoplasm. Because of the large size of the cell, the nucleus is often missed in the section, and only the cell cytoplasm is seen. PLATE 85KEY AMV, central adrenomedullary vein Cap, capillary GC, ganglion cells L, lumen of central adrenomedullary vein MC, medullary cells SM, smooth muscle TI, tunica intima TM, tunica media


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Histology_Ross. OVERVIEW OF THE MALE REPRODUCTIVE SYSTEM / 784 TESTIS / 784 Gender Determination and Development of the Testis / 785 Structure of the Testis / 788 Leydig Cells / 789 SPERMATOGENESIS / 792 Spermatogonial Phase / 792 Spermatocyte Phase (Meiosis) / 793 Spermatid Phase (Spermiogenesis) / 794 Structure of the Mature Sperm / 796 SEMINIFEROUS TUBULES / 798 Cycle of the Seminiferous Epithelium / 798 Waves of the Seminiferous Epithelium / 798 Sertoli Cells / 800 INTRATESTICULAR DUCTS / 802 EXCURRENT DUCT SYSTEM / 803 Epididymis / 803 Ductus Deferens / 807 ACCESSORY SEX GLANDS / 808 PROSTATE GLAND / 808 Bulbourethral Glands / 812 SEMEN / 813 PENIS / 813 Folder 22.1 Functional Considerations: Hormonal Regulation of Spermatogenesis / 788 Folder 22.2 Clinical Correlation: Factors Affecting Spermatogenesis / 789 Folder 22.3 Clinical Correlation: Sperm-Specific Antigens and the Immune Response / 803 Folder 22.4 Clinical Correlation: Benign Prostatic Hypertrophy and Cancer of the Prostate / 811


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Histology_Ross. / 789 Folder 22.3 Clinical Correlation: Sperm-Specific Antigens and the Immune Response / 803 Folder 22.4 Clinical Correlation: Benign Prostatic Hypertrophy and Cancer of the Prostate / 811 Folder 22.5 Clinical Correlation: Mechanism of Erection and Erectile Dysfunction / 815


Histology_Ross

Histology_Ross. The male reproductive system consists of the testes, genital excurrent ducts, accessory sex glands, and penis (Fig. 22.1). The accessory sex glands include the seminal vesicles, the prostate, and bulbourethral glands. The two primary functions of the testis are spermatogenesis (the production of sperm, called male gametes), and steroidogenesis (synthesis of androgens, also called sex hormones). Androgens, mainly testosterone, are essential for spermatogenesis, play an important role in embryonic development of the male embryo into the phenotypic male fetus, and are responsible for sexual dimorphism (male physical and behavioral characteristics). The events of cell division that occur during production of male gametes, as well as those of the female, the ova, involve both normal division, mitosis, and reduction division, meiosis.


Histology_Ross

Histology_Ross. The events of cell division that occur during production of male gametes, as well as those of the female, the ova, involve both normal division, mitosis, and reduction division, meiosis. A brief description of mitosis and meiosis is included in Chapter 3. A basic understanding of these processes is essential to understanding the production of gametes in both men and women. The adult testes are paired ovoid organs that lie within the scrotum, located outside the body cavity. Each testis is suspended within the end of an elongated musculofacial pouch, which is continuous with layers of the anterior abdominal FIGURE 22.1 • Schematic diagram demonstrating the components of the male reproductive system. Midline structures are depicted in sagittal section; bilateral structures including the testis, epididymis, ductus deferens, and seminal vesicle are shown intact.


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Histology_Ross. wall and projects into the scrotum. Testes are connected by the spermatic cords to the abdominal wall and tethered to the scrotum by scrotal ligaments, the remnants of the gubernaculum (see further in the chapter). Gender Determination and Development of the Testis Gender differentiation is accomplished through a cascade of gene activations. Genetic sex is determined at fertilization by the presence or absence of the Y chromosome. The testes, however, do not form until the seventh week of development. Gonadal sex is determined by the presence of the SRY gene located in the sex-determining region of the short arm of the Y chromosome. The SRY gene expression in early embryonic development is responsible for gender determination.


Histology_Ross

Histology_Ross. The genetic information encoded in the Y chromosome itself is not sufficient to guide a complex development of the male gonads. Instead, the SRY gene operates as a master switch that controls the cascade of several gene activations on autosomes 9, 11, 17, and 19 and the X chromosome. A transcription factor called the testis-determining factor (TDF), encoded by the SRY gene, has a molecular domain that binds into a specific region of DNA and alters it structure. The affected DNA forms a loop that permits binding of other transcription factors. They in turn cause the expression of other genes that initiate formation of not only the testes but also other male sex organs. Several other genes are expressed about the same time as the SRY gene, including these:  WT-1 gene, that is required for the development of the urogenital system and for regulation of the SRY transcrip tion. Mutations of the WT-1 gene are found in children with familial Wilms’s tumor and in children with accompanied


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Histology_Ross. the development of the urogenital system and for regulation of the SRY transcrip tion. Mutations of the WT-1 gene are found in children with familial Wilms’s tumor and in children with accompanied genitourinary malformations.


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Histology_Ross.  SOX-9 gene found in the genital ridges activates the AMH gene that is responsible for Mlerian-inhibiting factor synthesis. The mutation of the SOX9 gene is linked to a reversal of the gender of a male individual (46, XY).  SF-1 gene (steroidogenic factor-1 gene) that regulates the expression of a number of steroidogenic genes.  DAX-1 gene that encodes nuclear receptor DAX-1. Acti vation of this receptor suppresses the SRY gene during gonadal sex differentiation and its mutation is responsible for congenital adrenal hypoplasia. The testes develop on the posterior wall of the abdomen and later descend into the scrotum.


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Histology_Ross. The testes develop on the posterior wall of the abdomen and later descend into the scrotum. The testes develop in close association with the urinary system retroperitoneally on the posterior wall of the abdominal cavity. Testes (like ovaries) are derived from three sources:  Intermediate mesoderm that forms the urogenital ridges on the posterior abdominal wall, giving rise to Leydig cells (interstitial cells) and myoid cells (peritubular contractile cells) that lines the urogenital ridges and gives rise to Sertoli cells  Primordial germ cells that migrate from the yolk sac into developing gonads, where they divide and differentiate into spermatogonia


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Histology_Ross. Migration of the primordial germ cells into the genital ridges induces mesodermal cells of the urogenital ridges and cells of the coelomic mesothelium to proliferate and form the primary sex cords. At this stage, these cords are comprised of primordial germ cells, pre-Sertoli cells, and a surrounding layer of myoid cells. Later, primary sex cords duct of epididymis degenerating paramesonephric duct


Histology_Ross

Histology_Ross. FIGURE 22.2 • Schematic diagram of the stages of testicular development. a. This diagram shows the 5-week embryo in the stage of indifferent gonads. The gonadal ridges visible on the posterior abdominal wall are being infiltrated by primordial germ cells (green) that migrate from the yolk sac. Most of the developing gonad is formed by mesenchyme derived from the coelomic epithelium. The primordial germ cells become incorporated in the primary sex cords. b. At a later stage, under hormonal influence of testis-determining factor (TDF), the developing gonad initiates production of testosterone. This is followed by differentiation of the primary sex cords into seminiferous cords. At the same time, the developing gonad produces Mlerian-inhibiting factor (MIF), which causes regression of the paramesonephric duct and those structures derived from it. Note that the mesonephric tubules come in close contact with the developing rete testis. c. Final stages of testicular development. The tunica


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Histology_Ross. duct and those structures derived from it. Note that the mesonephric tubules come in close contact with the developing rete testis. c. Final stages of testicular development. The tunica albuginea surrounding the testis contributes to development of the testicular septa. The rete testis connects with the seminiferous cords and with the excurrent duct system that develops from the mesonephric duct and tubules.


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Histology_Ross. differentiate into the seminiferous cords, which give rise to the seminiferous tubules, straight tubules, and rete testis (Fig. 22.2).


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Histology_Ross. In the first stage of development, the testes develop on the posterior abdominal wall from indifferent primordia of urogenital ridges that are identical in both sexes. During this indifferent stage an embryo has the potential to develop into either a male or female. However, expression of the SRY gene—exclusively in the pre-Sertoli cells—orchestrates male development of the embryo. Early in male development, mesenchyme separating the seminiferous cords gives rise to Leydig (interstitial) cells that produce testosterone to stimulate development of the indifferent primordium into a testis. Testosterone is also responsible for the growth and differentiation of the mesonephric (Wolffian) ducts that develop into the male genital excurrent ducts. Also in this early stage, the Sertoli (sustentacular) cells that develop within the seminiferous cords produce another important hormonal substance, called Mlerian-inhibiting factor (MIF). MIF’s molecular structure is similar to that of


Histology_Ross

Histology_Ross. (sustentacular) cells that develop within the seminiferous cords produce another important hormonal substance, called Mlerian-inhibiting factor (MIF). MIF’s molecular structure is similar to that of transforming growth factor(TGF-). It is a large glycoprotein that inhibits cell division of the paramesonephric (Mlerian) ducts, which in turn inhibits development of female reproductive organs (Fig. 22.3).


Histology_Ross

Histology_Ross. Development and differentiation of the external genitalia (also from the sexually indifferent stage) occur at the same time and result from the action of dihydrotestosterone (DHT), a product of the conversion of testosterone by 5reductase. Without DHT, regardless of the genetic or gonadal sex, the external genitalia will develop along the female template. The appearance of testosterone, MIF, and DHT in the developing male embryo determines its hormonal sex. (Folder 22.1)


Histology_Ross

Histology_Ross. At approximately the 26th week of gestation, the testes descend from the abdomen into the scrotum. This migration of testes is caused by differential growth of the abdominal cavity combined with the action of testosterone that causes shortening of the gubernaculum, the testosterone-sensitive ligament connecting the inferior pole of each testis with the developing scrotum. The testes descend into the scrotum by passing through the inguinal canal, the narrow passage between the abdominal cavity and the scrotum. During descent, the testes carry their blood vessels, lymphatic vessels, and nerves as well as their principal ex-current duct system, the ductus deferens with them. Descent of the testis is sometimes obstructed, resulting in cryptorchidism, or undescended testes. This condition is common (30%) in premature newborns and about 1% of fullterm newborns. Cryptorchidism can lead to irreversible histologic changes in the testis and increases the risk of testicular cancer. Therefore,


Histology_Ross

Histology_Ross. common (30%) in premature newborns and about 1% of fullterm newborns. Cryptorchidism can lead to irreversible histologic changes in the testis and increases the risk of testicular cancer. Therefore, an undescended testis requires surgical correction. Orchiopexy (placement in the scrotal sac) should be performed, preferably before histologic changes become irreversible at approximately 2 years of age.


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Histology_Ross. Spermatogenesis requires that the testes be maintained below normal body temperature. As the testes descend from the abdominal cavity into the scrotum, they carry with them blood vessels, lymphatic vessels, autonomic nerves, and an extension of the abdominal peritoneum called the tunica vaginalis, which covers their anterolateral surface. Within the scrotum the temperature of the testes is 2C to 3C below body temperature. This lower temperature is essential for spermatogenesis, but is not required for hormone production (steroidogenesis), which can occur at normal body temperature. If the testes are maintained at higher temperatures (e.g., because of fever) or if they fail to descend into the scrotum, sperm are not produced.


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Histology_Ross. Each testis receives blood through a testicular artery, a direct branch of the abdominal aorta. It is highly convoluted near the testis, where it is surrounded by the pampiniform venous plexus, which carries blood from the testis to the abdominal veins. This arrangement allows heat exchange between the blood vessels and helps maintain the testes at a lower temperature. The cooler venous blood returning from the testis cools the arterial blood before it enters the testis through a countercurrent heat exchange mechanism. In addition, the cremaster muscle, whose fibers originate from the internal abdominal oblique muscle of the anterior abdominal wall, responds to changes in ambient temperature. Its contraction moves the testes closer to the abdominal wall, and its relaxation lowers the testes within the scrotum. Cold temperatures also cause contraction of a thin sheet of smooth muscle (dartos muscle) in the superficial fascia of the scrotum. Contraction of dartos


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Histology_Ross. FIGURE 22.3 • Schematic diagram of male sex development and hormonal infuence on developing reproductive organs. This diagram illustrates three levels on which the sex of the developing embryo is determined. The genetic sex is determined at the time of fertilization; gonadal sex is determined by activation of the SRY gene located on the short arm of chromosome Y; and hormonal sex is determined by a hormone secreted by the developing gonad. The diagram shows the influence of Mlerianinhibiting factor (MIF), testosterone, and dihydrotestosterone (DHT) on the developing structures.  FOLDER 22.1 Functional Considerations: Hormonal Regulation of Spermatogenesis


Histology_Ross

Histology_Ross. Normal function of testis is dependent upon hormones acting through endocrine and paracrine pathways. The endocrine function of the testis resides primarily in the Leydig cell pop-ulation that synthesizes and secretes the principal circulating androgen, testosterone. Nearly all of the testosterone is produced by the testis; less than 5% is produced by the adrenal glands. It is estimated in humans that the total Leydig cell population produces about 7 mg of testosterone per day. As testosterone leaves the Leydig cells, it passes into blood and lymphatic capillaries and across the peritubular tissue to reach the seminiferous epithelium. High local levels of testosterone within the testis (esti-mated to be as much as 200 times the circulating levels) are necessary for the proliferation and differentiation of sper-matogenic cells. This high testicular level of testosterone can be significantly decreased by negative feedback from exogenous testosterone. Intensive research in this area is


Histology_Ross

Histology_Ross. differentiation of sper-matogenic cells. This high testicular level of testosterone can be significantly decreased by negative feedback from exogenous testosterone. Intensive research in this area is being directed into development of a prototype of testos-terone-based contraceptive drugs for men. In early clinical studies, these drugs have been shown to cause a significant decrease in the testicular testosterone concentration and inhibition of spermatogenesis. Recovery of spermatogene-sis occurs after discontinuation of contraceptive use. How-ever, in some individuals, this type of contraceptive is not efficacious and does not cause spermatogenic suppression. Peripheral testosterone levels have the following effects:  Differentiation of the central nervous system (CNS) and the genital apparatus and genital excurrent duct system  Growth and maintenance of secondary sexual charac-teristics (such as the beard, male distribution of pubic hair, and low-pitched voice)  Growth and


Histology_Ross

Histology_Ross. apparatus and genital excurrent duct system  Growth and maintenance of secondary sexual charac-teristics (such as the beard, male distribution of pubic hair, and low-pitched voice)  Growth and maintenance of the accessory sex glands (seminal vesicles and prostate and bulbourethral glands), genital excurrent duct system, and the external genitalia (mainly byproducts of testosterone conversion to DHT)  Anabolic and general metabolic processes, including skeletal growth, skeletal muscle growth, distribution of subcutaneous fat, and kidney function  Behavior, including libido The steroidogenic and spermatogenic activities of the testis are regulated by hormonal interaction among the hy-pothalamus, anterior lobe of the pituitary gland, and gonadal cells (i.e., Sertoli, spermatogenic, and Leydig cells). The anterior lobe of the pituitary gland produces three hormones involved in this process: luteinizing hormone (LH), which in the male is sometimes referred to as interstitial


Histology_Ross

Histology_Ross. and Leydig cells). The anterior lobe of the pituitary gland produces three hormones involved in this process: luteinizing hormone (LH), which in the male is sometimes referred to as interstitial cell–stimulating hormone (ICSH); follicle-stimulating hormone (FSH); and prolactin (PRL). In response to LH release by the pituitary, Leydig cells pro-duce increasing amounts of testosterone. PRL acts in combination with LH to increase the steroidogenic activity of Leydig cells. Because FSH and testosterone receptors are found in Sertoli cells, these cells are the primary regu-lators of spermatogenesis.


Histology_Ross

Histology_Ross. muscles causes the scrotum to wrinkle when cold to help regulate heat loss (Folder 22.2). Structure of the Testis The testes have an unusually thick connective tissue capsule, the tunica albuginea. An unusually thick, dense connective tissue capsule, the tunica albuginea, covers each testis (Fig. 22.4). The inner part of this capsule, the tunica vasculosa, is a loose connective tissue layer that contains blood vessels. Each testis is divided into approximately 250 lobules by incomplete connective tissue septa that project from the capsule. Along the posterior surface of the testis, the tunica albuginea thickens and projects inward as the mediastinum testis. Blood vessels, lymphatic vessels, and the genital excurrent ducts pass through the mediastinum as they enter or leave the testis. Each lobule consists of several highly convoluted seminiferous tubules.


Histology_Ross

Histology_Ross. Each lobule consists of several highly convoluted seminiferous tubules. Each lobule of the testis consists of one to four seminiferous tubules, in which sperm are produced, and a connective tissue stroma, in which Leydig (interstitial) cells are contained (Fig. 22.5). Each tubule within the lobule forms a loop and, because of its considerable length, is highly convoluted, actually folding on itself within the lobule. The ends of the loop are located near the mediastinum of the testis, where they assume a short straight course. This part of the seminiferous tubule is called the straight tubule (tubulus rectus). It becomes continuous with the rete testis, an anastomosing channel system within the mediastinum. The seminiferous tubules consist of a seminiferous epithelium surrounded by a tunica propria.


Histology_Ross

Histology_Ross. The seminiferous tubules consist of a seminiferous epithelium surrounded by a tunica propria. Each seminiferous tubule is approximately 50 cm long (range, 30 to 80 cm) and 150 to 250 m in diameter. The seminiferous epithelium is an unusual and complex stratified epithelium composed of two basic cell populations:  Sertoli cells, also known as supporting, or sustentacular, cells. These cells do not replicate after puberty. Sertoli cells are columnar cells with extensive apical and lateral processes that surround the adjacent spermatogenic cells and occupy the spaces between them. However, this elaborate configuration of the Sertoli cells cannot be seen distinctly in routine hematoxylin and eosin (H&E) preparations.


Histology_Ross

Histology_Ross. Degenerative changes, such as apoptosis, premature sloughing of cells, or formation of multinucleated giant cells, are readily apparent after exposure to such agents. Factors that negatively affect spermatogenesis include these:  Dietary defciencies. Reduced dietary intake is known to impair spermatogenesis. Vitamins, coenzymes, and microelements such as vitamin A, B12, C, E, -carotenes, zinc, and selenium have been shown to affect sperm formation.  Environmental/lifestyle factors. A recent study con-ducted in Denmark compared the sperm count in two groups of young men from rural and urban populations. A higher median sperm count (24%) was found in the men from the rural group compared with those from the urban group.  Developmental disorders. Cryptorchidism, hypospa-dias, and factors such as low birth weight have been found to be important risk factors for testicular cancer associated with reduced semen quality and reduced fertility.  Systemic diseases or local infections.


Histology_Ross

Histology_Ross. such as low birth weight have been found to be important risk factors for testicular cancer associated with reduced semen quality and reduced fertility.  Systemic diseases or local infections. Infections involving the testis (orchitis) may have an effect on sper-matogenesis. Systemic diseases that can impair sper-matogenesis include fever, kidney diseases, HIV and other viral infections, and metabolic disorders.  Elevated testicular temperature. A sedentary lifestyle may impair the ability to maintain the lower temperature of the testis in the scrotum. A higher than average scrotal temperature has been linked to failure of spermatogenesis. sure to synthetic estrogen (diethylstilbestrol) and other sex steroids can exert negative feedback on FSH secre-tion, resulting in decreased spermatogenesis. Prenatal exposure to estrogens can potentially inhibit fetal go-nadotropin secretion and inhibit Sertoli cell proliferation.  Toxic agents. Mutagenic agents, antimetabolites, and some


Histology_Ross

Histology_Ross. Prenatal exposure to estrogens can potentially inhibit fetal go-nadotropin secretion and inhibit Sertoli cell proliferation.  Toxic agents. Mutagenic agents, antimetabolites, and some pesticides, e.g., dibromochloropropane (DBCP), can drastically affect spermatogenesis and production of normal sperm. DBCP is a nematocide pesticide that is still used in some developing countries. It has been shown to cause a major decrease in sperm count and infertility after human exposure. Other agents that may affect fertility include chemicals in plastics (e.g., phtha-lates), pesticides (e.g., DDT), products of combustion (e.g., dioxins), polychlorinated biphenyls (PCBs), and others. Most of these chemicals possess very weak estrogen properties and may affect fertility. Direct toxic-ity to the spermatogonia is linked to changes in sperm quality.  Ionizing radiation and alkylating agents. Nitrogen mustard gas and procarbazine have been found to have toxic effects on spermatogonia. Electromagnetic


Histology_Ross

Histology_Ross. is linked to changes in sperm quality.  Ionizing radiation and alkylating agents. Nitrogen mustard gas and procarbazine have been found to have toxic effects on spermatogonia. Electromagnetic and mi-crowave radiation also affect sperm count and motility. Proliferating cells are particularly sensitive to mutagenic agents and the absence of essential metabolites. There-fore, nondividing Sertoli cells, Leydig cells, and reserve stem cells, which demonstrate low mitotic activity, are much less vulnerable than actively dividing, differentiating spermatogenic cells.


Histology_Ross

Histology_Ross.  FOLDER 22.2 Clinical Correlation: Factors Affecting Spermatogenesis Spermatogenic cells are very sensitive to noxious agents.  Steroid hormones and related medications. Expo- Sertoli cells give structural organization to the tubules as they extend through the full thickness of the seminiferous epithelium.  Spermatogenic cells, which regularly replicate and differentiate into mature sperm. These cells are derived from primordial germ cells originating in the yolk sac that colonize the gonadal ridges during early development of the testis. Spermatogenic cells are organized in poorly defined layers of progressive development between adjacent Sertoli cells (Fig. 22.6). The most immature spermatogenic cells, called spermatogonia, rest on the basal lamina. The most mature cells, called spermatids, are attached to the apical portion of the Sertoli cell, where they border the lumen of the tubule.


Histology_Ross

Histology_Ross. The tunica (lamina) propria, also called peritubular tissue, is a multilayered connective tissue that lacks typical fibroblasts. In man, it consists of three to five layers of myoid cells (peritubular contractile cells) and collagen fibrils, external to the basal lamina of the seminiferous epithelium (see Fig. 22.6). At the ultrastructural level, myoid cells demonstrate features associated with smooth muscle cells, including a basal lamina and large numbers of actin filaments. They also exhibit a significant amount of rough endoplasmic reticulum (rER), a feature indicating their role in collagen synthesis in the absence of typical fibroblasts. Rhythmic contractions of the myoid cells create peristaltic waves that help move spermatozoa and testicular fluid through the seminiferous tubules to the excurrent duct system. Blood vessels and extensive lymphatic vasculature as well as Leydig cells are present external to the myoid layer.


Histology_Ross

Histology_Ross. As a normal consequence of aging, the tunica propria increases in thickness. This thickening is accompanied by a decreased rate of sperm production and an overall reduction in the size of the seminiferous tubules. Excessive thickening of the tunica propria earlier in life is associated with infertility. Leydig cells (interstitial cells) are large, polygonal, eosinophilic cells that typically contain lipid droplets (Fig. 22.7). head of


Histology_Ross

Histology_Ross. Leydig cells (interstitial cells) are large, polygonal, eosinophilic cells that typically contain lipid droplets (Fig. 22.7). head of FIGURE 22.4 • Sagittal section of the human testis. a. This schematic diagram shows a midsagittal section of the human testis. The genital duct system, which includes the tubuli recti, rete testis, efferent ducts, duct of the epididymis, and ductus deferens, is also shown. Note the thick connective tissue covering, the tunica albuginea, and the surrounding tunica vaginalis. (Modified from Dym M. In: Weiss L, ed. Cell and Tissue Biology: A Textbook of Histology, 6th ed. Baltimore: Urban & Schwarzenberg, 1988.) b. Sagittal section of an H&E–stained section of the testis and the head and body of the epididymis. Again note the surrounding tunica albuginea and tunica vaginalis. Only a small portion of the rete testis is visible in this section. Its connection with the excurrent duct system is not evident in the plane of this section. 3.


Histology_Ross

Histology_Ross. Lipofuscin pigment is also frequently present in these cells as well as distinctive, rod-shaped cytoplasmic crystals, the crystals of Reinke (Fig. 22.8). In routine histologic preparations, these crystals are refractile and measure approximately 3 20 m. Although their exact nature and function remain unknown, they probably represent a protein product of the cell. Like other steroid-secreting cells, Leydig cells have an elaborate smooth endoplasmic reticulum (sER), a feature that accounts for their eosinophilia (see Fig. 22.7). The enzymes necessary for the synthesis of testosterone from cholesterol are associated with the sER. Mitochondria with tubulovesicular cristae, another characteristic of steroid-secreting cells, are also present in Leydig cells.


Histology_Ross

Histology_Ross. Leydig cells differentiate and secrete testosterone during early fetal life. Secretion of testosterone is required during embryonic development, sexual maturation, and reproductive function:  In the embryo, secretion of testosterone and other andro gens is essential for the normal development of the gonads in the male fetus.  At puberty, secretion of testosterone is responsible for the initiation of sperm production, accessory sex gland secre tion, and development of secondary sex characteristics. In the adult, secretion of testosterone is essential for the maintenance of spermatogenesis and of secondary sex char acteristics, genital excurrent ducts, and accessory sex glands.


Histology_Ross

Histology_Ross. The Leydig cells are active in the early differentiation of the male fetus and then undergo a period of inactivity beginning at about 5 months of fetal life. Inactive Leydig cells are difficult to distinguish from fibroblasts. When Leydig cells are exposed to gonadotropic stimulation at puberty, they again become androgen-secreting cells and remain active throughout life. Leydig cell tumors represents predominately benign tumors, which occur during two distinct periods (in childhood and in adults between 20 and 60 years old). They are hormonally active and secrete androgens or combination of androgens and estrogens. Commonly, they are composed of uniform cells with all characteristics of steroid hormone-secreting cells containing Reinke crystals. The frst symptom of these benign tumors, besides testicular enlargement, usually is related to abnormal level of hormone production. In prepubertal boys,


Histology_Ross

Histology_Ross. FIGURE 22.5 • Photomicrographs of human testis. a. This low-magnification photomicrograph of an H&E–stained section of a human testis shows seminiferous tubules and the tunica albuginea. The larger blood vessels are present in the inner aspect of the tunica albuginea. The seminiferous tubules are highly convoluted; thus the profiles that they present in the section are variable in appearance. 30. b. A higher magnification of the previous specimen shows several seminiferous tubules. Note the population of Leydig (interstitial) cells that occur in small clusters in the space between adjoining tubules. 250.


Histology_Ross

Histology_Ross. FIGURE 22.6 • Schematic drawing of human seminiferous epithelium. This drawing shows the relationship of the Sertoli cells to the spermatogenic cells. The seminiferous epithelium rests on a basal lamina, and a layer of peritubular cells surrounds the seminiferous tubule. The spermatogonia—type A pale, type A dark, and type B pale— and preleptotene spermatocytes are located in the basal compartment of the seminiferous epithelium below the junctional complex, between adjacent Sertoli cells. Pachytene primary spermatocytes, early spermatids, and late spermatids, with partitioning residual cytoplasm that becomes the residual body, are seen above the junctional complex in the abluminal compartment. (Redrawn from Clermont Y. The cycle of the seminiferous epithelium in man. Am J Anat 1963;112:35.) this leads to sexual precocity (unexpected pubertal changes in early age), whereas in adults it may be observed as feminization (development of female sexual characteristics) and gynecomastia


Histology_Ross

Histology_Ross. this leads to sexual precocity (unexpected pubertal changes in early age), whereas in adults it may be observed as feminization (development of female sexual characteristics) and gynecomastia (development of breast in males).


Histology_Ross

Histology_Ross. Spermatogenesis is the process by which spermatogonia develop into sperm. Spermatogenesis, the process by which sperm are produced, involves a complex and unique series of events. It begins shortly before puberty, under the influence of rising levels of pituitary gonadotropins, and continues throughout life. For descriptive purposes, spermatogenesis is divided into three distinct phases:  Spermatogonial phase, in which spermatogonia divide by mitosis to replace themselves as well as provide a popu lation of committed spermatogonia that will eventually


Histology_Ross

Histology_Ross. FIGURE 22.7 • Electron micrograph of Leydig cells. This electron micrograph shows portions of several Leydig cells. The cytoplasm contains an abundance of sER, a characteristic of Leydig cells. Other features characteristic of the Leydig cell seen in the lower-power micrograph are the numerous lipid droplets (L), the segmented profiles of the Golgi apparatus (G), and the presence of variable numbers of lysosomes (Ly). Occasional profiles of rER are also seen. Note also the presence of microvilli along portions of the cell surface (arrows). M, cytoplasm of adjacent macrophage. 10,000. Inset. sER at higher magnification. The very dense particles are glycogen. 60,000.  Spermatocyte phase (meiosis), in which primary sper matocytes undergo two meiotic divisions to reduce both the chromosome number and amount of DNA to produce haploid cells called spermatids Spermatid phase (spermiogenesis), in which sper


Histology_Ross

Histology_Ross. At the end of spermatogenesis, spermatids undergo their final maturation and are released during a process called spermiation from the supporting Sertoli cells into the lumen of the seminiferous tubule. In the spermatogonial phase, stem cells divide to replace themselves and provide a population of committed spermatogonia. Spermatogonial stem cells undergo multiple divisions and produce spermatogonial progeny that display differences in nuclear appearance in routine H&E preparations. FIGURE 22.8 • Electron micrograph of a Reinke crystal. This electron micrograph shows the internal structure of a Reinke crystal in the cytoplasm of a human Leydig cell. Also note the sER (arrows) and a lipid droplet (L) in the cytoplasm. 16,000. (Courtesy of Dr. Don F. Cameron.)


Histology_Ross

Histology_Ross. Human spermatogonia are classified into three types based on the appearance of the nuclei in routine histologic preparations:  Type A dark (Ad) spermatogonia have ovoid nuclei with intensely basophilic, finely granular chromatin. These spermatogonia are thought to be the stem cells of the seminiferous epithelium. They divide at irregular intervals to give rise to either a pair of type Ad spermatogonia that remain as stem cells or to a pair of type Ap spermatogonia.  Type A pale (Ap) spermatogonia have ovoid nuclei with lightly staining, finely granular chromatin. Ap spermatogonia are committed to the differentiation process that produces the sperm. They undergo several successive mitotic divisions, thereby increasing their number.  Type B spermatogonia have generally spherical nuclei with chromatin that is condensed into large clumps along the nuclear envelope and around a central nucleolus (see Fig. 22.6).


Histology_Ross

Histology_Ross.  Type B spermatogonia have generally spherical nuclei with chromatin that is condensed into large clumps along the nuclear envelope and around a central nucleolus (see Fig. 22.6). An unusual feature of the division of an Ad spermatogonium into two type Ap spermatogonia is that the daughter cells remain connected by a thin cytoplasmic bridge. This same phenomenon occurs through each subsequent mitotic and meiotic division of the progeny of the original pair of Ap spermatogonia (Fig. 22.9). Thus, all of the progeny of an initial pair of Ap spermatogonia are connected, much like a strand of pearls. These cytoplasmic connections remain intact to the last stages of spermatid maturation and are essential for the synchronous development of each clone from an original pair of Ap cells. After several divisions, type A spermatogonia differentiate into type B spermatogonia. The appearance of type B spermatogonia represents the last event in the spermatogonial phase.


Histology_Ross

Histology_Ross. After several divisions, type A spermatogonia differentiate into type B spermatogonia. The appearance of type B spermatogonia represents the last event in the spermatogonial phase. In the spermatocyte phase, primary spermatocytes undergo meiosis to reduce both the chromosome number and the amount of DNA. The mitotic division of type B spermatogonia produces primary spermatocytes. They replicate their DNA shortly after they form and before meiosis begins, so that each primary spermatocyte contains the normal chromosomal number (2n) and double the amount of DNA (4d ). Each chromosome consists of two sister chromatids; hence, 4d amount of DNA.


Histology_Ross

Histology_Ross. Meiosis I results in reduction of both the number of chromosomes (from 2n to 1n) and the amount of DNA to the haploid condition (from 4d to 2d); thus, secondary spermatocyte is characterized by haploid number of chromosomes (1n) and 2d amount of DNA. Because no DNA replication precedes meiosis II, after this division each spermatid has the haploid (1n) number of chromosomes, each containing a single chromatid (1d). Meiosis is described in detail in Chapter 3 (see page 89); a brief description of spermatocyte meiosis follows. Prophase of the first meiotic division, during which the chromatin condenses into visible chromosomes, lasts up to 22 days in human primary spermatocytes. At the end of prophase, 44 autosomes and an X and a Y chromosome, each having two chromatin strands (chromatids), can be identified. Homologous chromosomes are paired as they line up on the metaphase plate.


Histology_Ross

Histology_Ross. The paired homologous chromosomes, called tetrads because they consist of four chromatids, exchange genetic material in a process called crossing-over. During this exchange, the four chromatids rearrange into a tripartite structure called a synaptonemal complex. This process ensures genetic diversity. Through genetic exchange, the four spermatids produced from each spermatocyte differ from each other and from every other spermatid. After crossing-over is complete, the homologous chromosomes separate and move to the opposite poles of the meiotic spindle. Thus, the tetrads, which have been modified by crossing-over, separate and become dyads again. The two chromatids of each original chromosome (although modified by crossing-over) remain together. This is just the opposite of what happens in mitosis, in which the paired chromatids—one representing the “template” and the other, newly synthesized DNA—separate.


Histology_Ross

Histology_Ross. FIGURE 22.9 • Schematic diagram illus trating the generations of spermato genic cells. This diagram shows the clonal nature of the successive generations of spermatogenic cells. Cytoplasmic division is complete only in the primitive type A dark spermatogonia that serve as stem cells. All other spermatogenic cells remain connected by intercellular bridges as they undergo mitotic and meiotic division and differentiation of the spermatids. The cells separate into individual spermatozoa as they are released from the seminiferous epithelium. The residual bodies remain connected and are phagocytosed by the Sertoli cells. (Reprinted with permission from Dym M, Fawcett DW. Further observations on the numbers of spermatogonia, spermatocytes, and spermatids connected by intercellular bridges in the mammalian testis. Biol Reprod 1971;4:195–215.)


Histology_Ross

Histology_Ross. The movement of a particular chromosome of a homologous pair to either pole of the spindle is random (i.e., maternally derived chromosomes and paternally derived chromosomes do not sort themselves out at the metaphase plate). This random sorting is another source of genetic diversity in the resulting sperm.


Histology_Ross

Histology_Ross. The cells derived from the first meiotic division are called secondary spermatocytes. These cells immediately enter the prophase of the second meiotic division without synthesizing new DNA (i.e., without passing through an S phase; see pages 89–93). Each secondary spermatocyte has a reduced number of chromosomes to (1n), which is represented by 22 autosomes and an X or a Y chromosome. Each of these chromosomes consists of two sister chromatids. The secondary spermatocyte has the (2d), diploid amount of DNA. During metaphase of the second meiotic division, the chromosomes line up at the metaphase plate, and the sister chromatids separate and move to opposite poles of the spindle. As the second meiotic division is completed and the nuclear membranes re-form, two haploid spermatids, each containing 23 single-stranded chromosomes (1n) and the (1d) amount of DNA, are formed from each secondary spermatocyte (Fig. 22.10).


Histology_Ross

Histology_Ross. In the spermatid phase, spermatids undergo extensive cell remodeling as they differentiate into mature sperm. Each spermatid that results from the second meiotic division is haploid in DNA content (1d) and chromosome number (1n) represented by 22 autosomes and an X or Y chromosome. No further division occurs. The haploid spermatids undergo a differentiation process that produces mature sperm, which are also haploid. The normal diploid condition is restored when a sperm fertilizes an oocyte. The extensive cell remodeling that occurs during differentiation of the spermatid population into mature sperm (spermiogenesis) consists of four phases. These phases occur while the spermatids are physically attached to the Sertoli cell plasma membrane by specialized junctions. The morphologic changes in all four phases that occur during spermiogenesis are described here and summarized in Figure 22.11.