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Associated with Hyperthyroidism

Chapter 24 - The Endocrine System

Anirban Maitra MBBS

Abul K. Abbas MBBS

The endocrine system contains a highly integrated and widely distributed group of organs that orchestrates a state of metabolic equilibrium, or homeostasis, among the various organs of

the body. Signaling by extracellular secreted molecules can be classified into three types—autocrine, paracrine, or endocrine—on the basis of the distance over which the signal acts. In

endocrine signaling, the secreted molecules, which are frequently called hormones, act on target cells that are distant from their site of synthesis. An endocrine hormone is frequently

carried by the blood from its site of release to its target. Increased activity of the target tissue often down-regulates the activity of the gland that secretes the stimulating hormone, a

process known as feedback inhibition.

Hormones can be classified into several broad categories on the basis of the nature of their receptors. Cellular receptors and signaling pathways were discussed in Chapter 3 , and only a

few comments about signaling by hormone receptors follow:

Hormones that trigger biochemical signals upon interacting with cell-surface receptors: This large class of compounds is composed of two groups: (1) peptide hormones, such

as growth hormone and insulin, and (2) small molecules, such as epinephrine. Binding of these hormones to cell-surface receptors leads to an increase in intracellular signaling

molecules, termed second messengers, such as cyclic adenosine monophosphate (cAMP); production of mediators from membrane phospholipids, such as inositol 1,4,5-

trisphosphate or IP3 ; and shifts in the intracellular levels of ionized calcium. The elevated levels of one or more of these can control proliferation, differentiation, survival, and

functional activity of cells, mainly by regulating the expression of specific genes.

Hormones that diffuse across the plasma membrane and interact with intracellular receptors: Many lipid-soluble hormones diffuse across the plasma membrane and interact

with receptors in the cytosol or the nucleus. The resulting hormone-receptor complexes bind specifically to recognition elements in DNA, thereby affecting the expression of

specific target genes. Hormones of this type include the steroids (e.g., estrogen, progesterone, and glucocorticoids), and thyroxine.

A number of processes can disturb the normal activity of the endocrine system, including impaired synthesis or release of hormones, abnormal interactions between hormones and their

target tissues, and abnormal responses of target organs. Endocrine diseases can be generally classified as (1) diseases of underproduction or overproduction of hormones and their

resulting biochemical and clinical consequences and (2) diseases associated with the development of mass lesions. Such lesions might be nonfunctional, or they might be associated with

overproduction or underproduction of hormones. The study of endocrine diseases requires integration of morphologic findings with biochemical measurements of the levels of



hormones, their regulators, and other metabolites.

Pituitary Gland

Normal

The pituitary is a small bean-shaped organ that measures about 1 cm in greatest diameter and weighs about 0.5 gm, although it enlarges during pregnancy. Its small size belies its great

functional significance. It is located at the base of the brain, where it lies nestled within the confines of the sella turcica in close proximity to the optic chiasm and the cavernous sinuses.

The pituitary is attached to the hypothalamus by the pituitary stalk, which passes out of the sella through an opening in the dura mater surrounding the brain. Along with the

hypothalamus, the pituitary gland plays a critical role in

Figure 24-1Hormones released by the anterior pituitary. The adenohypophysis (anterior pituitary) releases five hormones that are in turn under the control of various stimulatory and

inhibitory hypothalamic releasing factors. TSH, thyroid-stimulating hormone (thyrotropin); PRL, prolactin; ACTH, adrenocorticotrophic hormone (corticotropin); GH, growth hormone

(somatotropin); FSH, follicle-stimulating hormone; LH, luteinizing hormone. The stimulatory releasing factors are TRH (thyrotropin-releasing factor), CRH (corticotropin-releasing

factor), GHRH (growth hormone-releasing factor), GnRH (gonadotropin-releasing factor). The inhibitory hypothalamic influences are comprised of PIF (prolactin inhibitory factor or

dopamine) and growth hormone inhibitory factor (GIH or somatostatin).

Figure 24-2 A, Photomicrograph of normal pituitary. The gland is populated by several distinct cell populations containing a variety of stimulating (trophic) hormones. B, Each of the

hormones has different staining characteristics, resulting in a mixture of cell types in routine histologic preparations. Immunostain for human growth hormone.

TABLE 24-1-- Classification of Pituitary Adenomas

Prolactin cell (lactotroph) adenoma

Growth hormone cell (somatotroph) adenoma

••Densely granulated GH cell adenoma

••Sparsely granulated GH cell adenoma with fibrous bodies

Thyroid-stimulating hormone cell (thyrotroph) adenomas

ACTH cell (corticotroph) adenomas

Gonadotroph cell adenomas

••Silent gonadotroph adenomas include most so-called null cell and oncocytic adenomas

Mixed growth hormone-prolactin cell (mammosomatotroph) adenomas

Other plurihormonal adenomas

Hormone-negative adenomas

ACTH, adrenocorticotropic hormone.

demonstration of lineage-specific differentiation. Both silent and hormone-negative pituitary adenomas may cause hypopituitarism as they encroach on and destroy adjacent anterior

pituitary parenchyma.

Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial neoplasms; they are discovered incidentally in up to 25% of routine autopsies. In fact, using highresolution

computed tomography or magnetic resonance imaging suggest that approximately 20% of "normal" adult pituitary glands harbor an incidental lesion measuring 3 mm or more

in diameter, usually a silent adenoma. [1] Pituitary adenomas are usually found in adults, with a peak incidence from the thirties to the fifties. Most pituitary adenomas occur as isolated

lesions. In about 3% of cases, however, adenomas are associated with multiple endocrine neoplasia (MEN) type 1 (discussed later). Pituitary adenomas are designated, somewhat

arbitrarily, microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter. Silent and hormone-negative adenomas are likely to come to

clinical attention at a later stage than those associated with endocrine abnormalities and are therefore more likely to be macroadenomas.

With recent advances in molecular techniques, substantial insight has been gained into the genetic abnormalities associated with pituitary adenomas:[2]

• The great majority of pituitary adenomas are monoclonal in origin, even those that are plurihormonal, suggesting that most arise from a single somatic cell. Some

plurihormonal tumors may arise from clonal expansion of primitive stem cells, which then differentiate in several directions simultaneously.

• G-protein mutations are possibly the best-characterized molecular abnormalities in pituitary adenomas. G-proteins are described in Chapter 3 ; here we will review their

function in the context of endocrine neoplasms. G-proteins play a critical role in signal transduction, transmitting signals from cell-surface receptors (e.g., GHRH receptor) to

intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (e.g., cyclic AMP, cAMP). These are heterotrimeric proteins, composed of a specific a-

subunit that binds guanine nucleotide and interacts with both cell surface receptors and intracellular effectors ( Fig. 24-3 ); the b- and g-subunits are noncovalently bound to the

specific a-subunit. Gs is a stimulatory G-protein that has a pivotal role in signal transduction in several endocrine organs, including the pituitary. The a-subunit of Gs (Gs a) is

encoded by the GNAS1 gene, located on chromosome 20q13. In the basal state, Gs exists as an inactive protein, with GDP bound to the guanine nucleotide-binding site of the a-

subunit of Gs . On interaction with the ligand-bound cell-surface receptor, GDP dissociates, and GTP binds to Gs a, activating the G-protein. The activation of Gs a results in the

generation of cAMP, which acts as a potent mitogenic stimulus for a variety of endocrine cell types (such as pituitary somatotrophs and corticotrophs, thyroid follicular cells,

parathyroid cells), promoting cellular proliferation and hormone synthesis and secretion. The activation of Gs a, and resultant generation of cAMP, are transient because of an

intrinsic GTPase activity in the a-subunit, which hydrolyzes GTP into GDP. A mutation in the a-subunit that interferes with its intrinsic GTPase activity will therefore result in

constitutive activation of Gs a, persistent generation of cAMP, and unchecked cellular proliferation ( Fig. 24-3 ). Approximately 40% of somatotroph cell adenomas bear

GNAS1 mutations that abrogate the GTPase activity of Gs a. The mutant form of GNAS1 is also known as the gsp oncogene because of its effects on tumorigenesis. In addition,

GNAS1 mutations have also been described in a minority of corticotroph adenomas; in contrast, GNAS1 mutations are absent in thyrotroph, lactotroph, and gonadotroph

adenomas, since their respective hypothalamic release hormones do not mediate their action via cAMP-dependent pathways.

• Multiple endocrine neoplasia (MEN) syndrome (discussed in detail below) is a familial disorder associated with tumors and hyperplasias of multiple endocrine organs,

including the pituitary. A subtype of MEN syndrome, known as MEN-1, is caused by germ line mutations of the gene MEN1, on chromosome 11q13. While MEN1 mutations

are, by definition, present in pituitary adenomas arising in context of the MEN-1 syndrome, they are uncommon in sporadic pituitary adenomas.

• Additional molecular abnormalities present in aggressive or advanced pituitary adenomas include activating mutations of the RAS oncogene and overexpression of the c-MYC

oncogene, suggesting that these genetic events are linked to disease progression.[3]

Figure 24-3The mechanism of G-protein mutations in endocrine neoplasia. Mutations in the G-protein-signaling pathway are seen in a variety of endocrine neoplasms, including

pituitary, thyroid, and parathyroid adenomas. G-proteins play a critical role in signal transduction, transmitting signals from cell-surface receptors (GHRH, TSH, or PTH receptor) to

intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (cAMP).

Figure 24-4Pituitary adenoma. This massive, nonfunctional adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctional

adenomas tend to be larger at the time of diagnosis than those that secrete a hormone.

Figure 24-5Pituitary adenoma. The monomorphism of these cells contrasts markedly with the mixture of cells seen in the normal anterior pituitary. Note also the absence of reticulin

network.

Figure 24-6Ultrastructural features of prolactinomas. A, Electron micrograph of a sparsely granulated prolactinoma. The tumor cells contain abundant granular endoplasmic reticulum

(indicative of active protein synthesis) and small numbers of secretory granules (6000X). B, Electron micrograph of densely granulated growth hormone-secreting adenoma. The tumor

cells are filled with large, membrane-bound secretory granules (6000X). (Courtesy of Dr. Eva Horvath, St. Michael's Hospital, Toronto, Ontario, Canada.)

Figure 24-7Homeostasis in the hypothalamus-pituitary-thyroid axis and mechanism of action of thyroid hormones. Secretion of thyroid hormones (T3 and T4 ) is controlled by trophic

factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus

and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 levels, in turn, suppress the secretion of both TRH and TSH.

This relationship is termed a negative-feedback loop. TSH binds to the TSH receptor on the thyroid follicular epithelium, which causes activation of G proteins, and cyclic AMP (cAMP)-

mediated synthesis and release of thyroid hormones (T3 and T4). In the periphery, T3 and T4 interact with the thyroid hormone receptor (TR) to form a hormone-receptor complex that

translocates to the nucleus and binds to so-called thyroid response elements (TREs) on target genes initiating transcription.

TABLE 24-2-- Disorders Associated with Thyrotoxicosis

Associated with Hyperthyroidism

Primary

••Diffuse toxic hyperplasia (Graves disease)

••Hyperfunctioning ("toxic") multinodular goiter

••Hyperfunctioning ("toxic") adenoma

••Hyperfunctioning thyroid carcinoma

••Iodine-induced hyperthyroidism

••Neonatal thyrotoxicosis associated with maternal Graves disease

Secondary

••TSH-secreting pituitary adenoma (rare) *


Date: 2016-04-22; view: 565


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