It had long been known that the pituitary gland regulates the functional activity of the thyroid gland and produces a hormone called thyroid-stimulating hormone, or thyrotropin (TSH), but it was only about 50 years ago that the adenohypophysial cell type that produces TSH was morphologically identified. In studies of the pituitaries of rats that had altered function of the thyroid and other glands, using periodic acid-Schiff (PAS) and various trichrome, aldehyde fuchsin (AF), and aldehyde thionin (AT) staining techniques, several investigators delineated the thyrotrophs in the rat pituitary anterior lobe (1,2). Subsequently, the fine structural features of rat thyrotrophs were revealed by transmission electron microscopy, and the ultrastructural alterations resulting from functional changes were disclosed (3). Several attempts were also made, through the application of these and other staining procedures, to identify the thyrotrophs in the human pituitary, but it became possible to do this after the introduction of immunocytochemistry and electron microscopy.
DEVELOPMENT AND ANATOMY
The thyrotrophs can be detected by immunocytochemistry during the 12th week of gestation in the anteromedial zone of the fetal pituitary (4). They become recognizable at about the same time as the gonadotrophs, after the appearance of the somatotrophs and corticotrophs and before that of the lactotrophs. Biologically active TSH is detected in the pituitary at 14 weeks of gestation. The thyrotrophs also develop in anencephalic fetuses, and tissue culture studies indicate that their differentiation and maturation are independent of the presence of hypothalamic hormones (5,6). During development, two populations of thyrotrophs cells are generated. A lineage not dependent on the presence of the transcription factor Pit-1 appears first in the rostral part of the gland and disappears by birth. The definitive Pit-1-dependent thyrotrophs appear later in the dorsal region of the gland and persist in the adult (7). In rats, mitoses of thyrotrophs contribute to the proliferation of the pituitary gland during the early postnatal period (8). Mitosis also has been demonstrated in the thyrotrophs of thyroidectomized adult rats and may be regulated by thyroxine (T4) and thyrotropin-releasing hormone (TRH) (9,10).
Several pituitary transcription factors and other factors have been identified that play important roles in the processes that direct organogenesis, cell commitment, proliferation, and differentiated function. Any or all of these substances are candidates for mutations causing pituitary dysfunction. Transcription factors like Pit-1, GATA-2, and PROP1 play a major role in the differentiation and maturation of thyrotrophs (11,12,13,14,15). These factors also play a role in cell-specific gene expression and regulation of the gene products, namely TSH (16,17). Other factors that may play a role in thyrotroph maturation and function include cleaved-prolactin variant and neurotensin (NT) (18,19). The autocrine/paracrine regulation of TSH secretion is evidenced by the pituitary bombesin-like peptide termed neuromedin B, which acts as a local regulator of TSH secretion. Neuromedin B is up-regulated by thyroid hormones and down-regulated by TRH (20,21).
In the human pituitary, the thyrotrophs represent 1% to 5% of all adenohypophysial cells. They are not randomly located throughout the gland, but are concentrated in the anteromedial portion of the mucoid wedge of the anterior lobe; thus, they are not in proximity to the posterior lobe. In this well-demarcated area, the thyrotrophs are the predominant cell type (Fig. 3.1) (22). They contain PAS-, AF- and AT-positive cytoplasmic granules, but they are less basophilic and less PAS-positive than the corticotrophs. They do not stain with acidophilic dyes, lead hematoxylin, erythrosin, or carmoisin. Immunocytochemistry is the most reliable method to reveal the presence of thyrotrophs by light microscopy (Fig. 3.2). In situ hybridization reveals the presence of estrogen receptor mRNA in nontumorous and adenomatous thyrotrophs (23).
FIGURE 3.1. Photomicrograph of a human pituitary gland, showing thyrotrophs concentrated in the anteromedial portion of the gland. The section was immunostained for thyrotropin (TSH) using the avidin-biotin-peroxidase method (magnification ×6).
FIGURE 3.2. Low-magnification (×250) and high-magnification (×400, inset) photomicrographs of an area of the anterior lobe of a human pituitary gland rich in thyrotropin (TSH)-immunoreactive cells with long cytoplasmic processes (avidin-biotin-peroxidase method).
By electron microscopy, the thyrotrophs are medium-sized or large, elongated cells with conspicuous cytoplasmic processes and centrally located spherical or ovoid nuclei (Fig. 3.3). The cytoplasm is abundant, and its rough-surfaced endoplasmic reticulum consists of randomly distributed, slightly dilated cisternae. The Golgi complex is located in the perinuclear area; its prominence varies depending on the hormonal activity of the cell. The mitochondria are rod shaped with regular transverse cristae and a moderately electron-dense matrix. Phagolysosomes are common. The secretory granules are small, most often measuring 100 to 200 nm. They are spherical, vary slightly in electron density, and are membrane bound with an electron-lucent halo between the electron-dense core and the limiting membrane. Secretory granule extrusions are not seen.
FIGURE 3.3. Electron photomicrograph of normal human thyrotrophs with euchromatic nuclei, well-developed cytoplasm, small secretory granules (100–200 nm), many of which are adjacent to the plasma membrane, and large phagolysosomes (magnification ×11,000; bar = 2 µm).
Immunocytochemistry shows strong immunoreactivity for the β-subunit of TSH and for the α-subunit, but not for other hormones (22). Immunoelectron microscopy confirms that the thyrotrophs contain TSH localized in the secretory granules. In the rat pituitary, a few cells that contain both immunoreactive growth hormone and TSH can be identified (24), suggesting a close link between somatotrophs and thyrotrophs, and raising the possibility that somatotrophs can transform to thyrotrophs. Consistent with this suggestion, in the pituitaries of rats made hypothyroid by administration of propylthiouracil, some somatotrophs degranulate and transform into thyroidectomy cells, exhibiting the ultrastructural signs of active secretion (25). Transdifferentiation of somatotrophs to thyrotrophs has also been found in the pituitary of humans with protracted primary hypothyroidism (26). These findings support the assumption that different adenohypophysial cell types cannot be conclusively separated and that under special conditions, one cell type may transform to another cell type and become able to produce the hormone characteristic of the latter cell type. Thus, the “one cell, one hormone” theory that dominated our thinking for several decades, which recognized five distinct cell types producing the six adenohypophysial hormones, is no longer accepted (22,27,28).
Thyrotrophs are present throughout life, and there are no major sex differences in their number, distribution, immunocytochemical profile, and histologic and ultrastructural features. They do not regress in old age, but continue to produce and release TSH (29). Indeed, the thyrotrophs are more prominent in older people in whom the incidence of subclinical and overt hypothyroidism is higher than in young or middle-aged people.
EFFECT OF THYROID DISORDERS ON PITUITARY MORPHOLOGY
Changes in the secretion of TSH markedly affect the morphology of the thyrotrophs. In patients with long-standing primary hypothyroidism, the thyrotrophs increase in number and size (30) (Figs. 3.4 and 3.5). Reticulin stains show enlarged acinar structures without compression of surrounding tissue (Fig. 3.6). The large thyrotrophs have an abundant vacuolated cytoplasm and long, prominent cytoplasmic processes, and they contain many large, strongly PAS-positive cytoplasmic globules, which are in fact large lysosomes. These latter structures, however, may occur in other conditions and in other cell types as well (24,31,32).
FIGURE 3.4. Photomicrograph of thyrotroph hyperplasia in the pituitary of a patient with hypothyroidism, showing large acinar structures formed by columnar cells possessing abundant, slightly vacuolated cytoplasm (hematoxylin and eosin, magnification ×220).
FIGURE 3.5. Photomicrograph of thyrotroph hyperplasia in the pituitary of a patient with hypothyroidism. The enlarged acini contain numerous cells intensely or moderately immuno-stained for thyrotropin (TSH) (avidin-biotin-peroxidase method, magnification ×250).
FIGURE 3.6. Reticulin-stained section of thyrotroph hyperplasia in the pituitary of a patient with hypothyroidism, showing enlarged acinar structures and loosened reticulin network (magnification ×100).
Thyrotroph hyperplasia may be diffuse or nodular; the thyrotroph area within the anterior lobe enlarges, and the thyrotrophs extend to other parts of the anterior lobe. The extent of thyrotroph hypertrophy and hyperplasia may be sufficient to cause radiologically detectable enlargement of the pituitary and occasionally even optic nerve compression. Massive thyrotroph hyperplasia due to primary hypothyroidism thus may be difficult to distinguish clinically from a pituitary tumor causing central (secondary) hypothyroidism. Also, several patients with marked thyrotroph hyperplasia have been misdiagnosed as having prolactin-secreting pituitary adenomas because patients with long-standing primary hypothyroidism may have amenorrhea, galactorrhea, and hyperprolactinemia as well as pituitary enlargement (33,34).
By electron microscopy, the hypertrophic and hyperplastic thyrotrophs of patients with hypothyroidism show different degrees of dilatation and vesiculation of the endoplasmic reticulum, a prominent Golgi complex, and normal mitochondria. Also, compared with normal thyrotrophs, the secretory granules are less numerous and are similar in size or are slightly enlarged (Fig. 3.7). No exocytosis is seen (24).
FIGURE 3.7. Electron photomicrograph of stimulated thyrotrophs in the pituitary of a patient with hypothyroidism. The rough endoplasmic reticulum is well developed and dilated or vesiculated. A lactotroph is shown at the bottom of the micrograph (magnification ×9,000; bar = 2 µm).
In hypothyroid rats, the thyrotrophs also are large and have pale, vacuolated cytoplasm. Neurofilaments (NF-H) are seen in the thyrotrophs of hypothyroid rats, and discontinuation of antithyroid treatment leads to disappearance of the filaments (35). Electron microscopy reveals prominent endoplasmic reticulum membranes and Golgi complexes. The endoplasmic reticulum is dilated and vesiculated. The secretory granules in these thyrotrophs are small and sparse, measuring 50 to 150 nm (24). These stimulated cells are called thyroidectomy or thyroid deficiency cells and are assumed to represent hyperactive cells due to protracted stimulation secondary to the lack of negative feedback action of thyroid hormone (24). Occasionally, thyrotroph hyperplasia may progress to adenoma formation, suggesting that protracted stimulation may not only increase TSH synthesis and release, as well as cell proliferation, but also cause neoplastic transformation (34).
In humans and animals with primary hypothyroidism, thyroid hormone therapy results in regression of the morphologic changes in the pituitary, indicating that the hypertrophy and hyperplasia of thyrotrophs are reversible. This reversal is partly due to reversal of transdifferentiation and partly due to apoptosis (36).
The morphology of thyrotrophs in TRH deficiency has not yet been described in humans. In this situation, TSH secretion is decreased, and one would expect this decrease to be accompanied by morphologic changes that reflect decreased functional activity. A recent study of mice with congenital TRH deficiency revealed that TRH is not essential for fetal thyroid development, but is essential for normal postnatal thyrotroph function, including normal feedback regulation of the TSH gene by thyroid hormone (37,38).
In patients with a rare familial form of dwarfism characterized by hypothyroidism and prolactin deficiency, the pituitary contains no somatotrophs, lactotrophs, and thyrotrophs (see section on congenital hypothyroidism in Chapter 75) (39). This syndrome is caused by mutation of the pit-1 gene (40,41). The simultaneous absence of these cells confirms the close lineal relationship among these three types of adenohypophysial cells.
Pituitary morphology has not been studied much in patients with thyrotoxicosis. In 1966, Murray and Ezrin (42) described the light microscopic features of thyrotrophs in patients with thyrotoxicosis caused by Graves' disease. Using conventional histology as well as AT staining, they demonstrated regression of thyrotrophs in these patients. Well-granulated thyrotrophs could not be identified, and the cells resembling thyrotrophs were small and had small nuclei, a thin rim of cytoplasm, and a few AT-positive vesicles. Immunocytochemical studies confirmed the reversible involution of thyrotrophs in patients with Graves' disease (43).
In other endocrine or nonendocrine diseases, the thyrotrophs are not altered. For example, in patients with primary adrenal insufficiency or primary hypogonadism, the number, size, distribution, and morphologic appearance of the thyrotrophs are normal. Similarly, the thyrotrophs are normal in patients with pituitary tumors not associated with TSH hypersecretion.
Thyrotroph adenomas are the rarest type of anterior pituitary tumor (31,44,45), and one case of a thyrotroph carcinoma has been described (46). It is not clear why adenomas arise less frequently in thyrotrophs than in other cell types. Thyrotroph adenomas may develop in association with thyrotoxicosis or hypothyroidism (47,48,49,50), and the adenomas in both types of patients have similar morphologic features.
At the time of discovery, thyrotroph adenomas in patients with thyrotoxicosis range in size from microadenomas to large macroadenomas that occupy the entire sella turcica and may extend above it or invade neighboring structures. The adenomas are usually well demarcated from the surrounding pituitary tissue, because they are surrounded by a pseudocapsule that consists of condensed reticulin fibers and a few rows of compressed nontumorous adenohypophysial cells. The adenoma cells are chromophobic (Fig. 3.8) and contain a few small PAS-positive cytoplasmic granules or, occasionally, large PAS-positive lysosomal globules. Immunocytochemistry demonstrates the presence of TSH in the cytoplasm of the adenoma cells (Fig. 3.9) in most tumors, but in some tumors the adenoma cells cannot be immunostained, suggesting either loss of TSH during fixation and embedding or production of an abnormal TSH that is not immunoreactive (22). Nontumorous and adenomatous thyrotrophs express pit-1, the transcription factor responsible for the development and maturation of thyrotrophs. Although it plays no major role in the pathogenesis of thyrotroph adenomas, the invariable expression of the pit-1 protein in TSH-positive adenomas suggest that it plays a role in differentiation of the adenoma cells (51,52,53).
FIGURE 3.8. Photomicrograph of a thyrotroph adenoma. The chromophobic cells are disposed in pseudorosettes around vessels (hematoxylin and eosin, magnification ×250).
FIGURE 3.9. Photomicrograph of a thyrotroph adenoma. Most cells contain immunoreactive thyrotropin (TSH) (avidin-biotin-peroxidase method, magnification ×250).
By electron microscopy, thyrotroph adenomas are composed of middle-sized or large, usually well-differentiated, moderately polar, elongated cells that have spherical nuclei showing focal pleomorphism and prominent nucleoli as well as abundant cytoplasm with long cytoplasmic processes (Fig. 3.10). The cytoplasm contains well-developed rough endoplasmic reticulum membranes. The Golgi complexes, poorly represented in some tumors but well developed in others, are located in the perinuclear area and are composed of sacs, vesicles, and a few immature secretory granules. The mitochondria are ovoid or spherical, with transverse cristae and a moderately electron-dense matrix. The secretory granules are mostly spherical and usually small, measuring 100 to 200 nm in diameter (Fig. 3.10); occasionally, adenomas have larger secretory granules (up to 400 nm). The secretory granules accumulate in the cytoplasmic processes and are often located in a single row underneath the plasmalemma, but granule exocytosis is not seen.
FIGURE 3.10. Electron photomicrograph of a thyrotroph adenoma, showing thyrotrophs with indented nuclei containing large nucleoli and long cytoplasmic processes. Small secretory granules are present at the periphery of the cytoplasm (magnification ×5,000; bar = 2 µm).
Thyrotroph adenomas rarely contain thyroidectomy cells. In a few tumors, however, usually in hypothyroid or euthyroid patients, the adenoma cells have the appearance of typical thyroidectomy cells. The importance of thyroidectomy cells in thyrotroph adenomas is not known, but the finding could reflect the absence of thyroid hormone receptors in the tumors. The absence of thyroidectomy cells in most tumors may reflect immaturity or the absence of TRH receptors (54).
With the wider use of immunocytochemistry and electron microscopy, it has become evident that TSH-producing cells occur often in other hormone-secreting pituitary adenomas (27,31,55,56), especially adenomas that contain growth hormone, TSH, and α-subunit. Most of these tumors are composed of densely granulated somatotrophs and are associated with acromegaly (57). There are also adenomas that contain growth hormone or prolactin, or both, along with TSH and α-subunit, with the structural features of glycoprotein-producing adenomas (31) (Fig. 3.11). Ultrastructurally, they are monomorphic adenomas that consist of cells with the characteristics of thyrotrophs (31,58). Such tumors may be associated with acromegaly and thyrotoxicosis (31,57,58). Plurihormonal adenomas composed of different cell types indicating multidirectional differentiation have also been described (Fig. 3.12) (59); usually, the expressed hormones are not secreted in clinically important amounts. Null cell adenomas and oncocytomas often have a few scattered cells or groups of cells that contain immunoreactive TSH (31). These clinically nonfunctioning tumors are thought to be derived from an uncommitted precursor cell, which may undergo multi-directional differentiation and produce various hormones, including TSH.
FIGURE 3.11. Photomicrograph of a glyco-protein-producing pituitary adenoma containing scattered thytropin (TSH)-immunoreactive cells (avidin-biotin-peroxidase method, magnification ×250). This tumor also contained growth hormone and α-subunit (not shown).
FIGURE 3.12. Electron micrograph of a plurihormonal adenoma containing cells with features of thyrotrophs (TSH) and somatotrophs (GH). The thyrotrophs contain small secretory granules lined up along the cell membranes (right). The cell with randomly arranged large secretory granules (left) is a somatotroph (magnification ×11,000).
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