The Endocrine System

Chapter 18 The Endocrine System

Ivan Damjanov, MD, PhD

2 What are hormones?

Hormones are biologically active substances secreted by one cell that stimulate other cells. Traditionally this term was reserved for endocrine substances (i.e., secreted into the blood and carried by circulation to their distant target organs). This concept was broadened and today includes a variety of substances that exert:

Paracrine stimulation (i.e., act on adjacent cells in the tissue of their origin)

Autocrine stimulation (i.e., act on the cell that has produced the substance)

Neurocrine stimulation (i.e., substances produced by neurons that act on nonneuronal cells)

Figure 18-1 Hormonal stimulation. A, Endocrine. The hormones are carried by blood from the cell that has produced the hormone to the distant target. B, Paracrine. The hormone produced by one cell acts on an adjacent cell. C, Autocrine. The hormone acts on the cell that has produced it. D, Neurocrine. The hormone released from a nerve cell acts on an endocrine cell.

4 What are the differences between peptide and amine hormones versus steroid hormones?

In general, peptide and amine hormones are stored inside the cells of their origin in the form of dense neuroendocrine granules that can be seen by electron microscopy. These hormones act on receptors on the plasma membrane of target cells, which in turn activate a signaling system in the cytoplasm. The impulse is transmitted from the plasma membrane to the DNA by secondary messengers. In contrast to these hormones, steroids are not stored in granules but are synthesized on external stimulation by trophic hormones (e.g., adrenocorticotropic hormone [ACTH] stimulates the synthesis of glucocorticoids). Steroid hormones have receptors in the nucleus of their target cells, and their action on the nuclear DNA does not require activation of a cytoplasmic messenger system. See Fig. 18-2.

Figure 18-2 Electron microscopic photograph of neuroendocrine cells. The cytoplasm contains membrane-bound dark neuroendocrine granules, which typically contain polypeptide hormones.

6 Is the enlargement of endocrine glands always associated with their hyperfunction?

The enlargement of endocrine glands may be accompanied by overproduction of hormones, no obvious hormonal changes, or reduced hormonal output. For example, thyroid enlargement in Graves disease is associated with hyperthyroidism. Nodular goiter is most often euthyroid. Anaplastic carcinoma may completely destroy the normal thyroid and cause hypothyroidism.

PITUITARY

7 Where is the normal pituitary located?

The pituitary is located in the sella turcica, a concavity of the sphenoid bone that forms a part of the base of the skull. Enlargement of the pituitary can cause an expansion of the sella turcica that can be seen by x-ray.

8 To which other organ is the pituitary anatomically linked?

The pituitary is attached to the brain by a stalk, composed of blood vessels of the pituitary portal system and axonal extensions of hypothalamic nerves. Transection of the pituitary stalk causes hypopituitarism. It will hinder the influx of blood that contains the hypothalamic-releasing factors (i.e., neuropeptides that normally stimulate the cells in the anterior lobe of the pituitary). The transection of axons that serve as conduits for the transport of oxytocin and antidiuretic hormone (ADH) from the hypothalamus into the posterior lobe of the pituitary will prevent the entry of these hormones into the blood and thus cause diabetes insipidus.

9 Why does enlargement of the pituitary impair vision?

Enlargement of the pituitary will cause compression of the optic chiasm, which is overlying the membranous covering of the sella turcica. Compression of the central portion of the chiasm leads to a loss of lateral visual fields of both eyes, known as bilateral hemianopsia.

10 What are the main cell types of the pituitary?

The anterior pituitary consists of four functional cell types that can be identified immunohistochemically using the antibodies to specific pituitary hormones. These cells are:

Somatotrophs, producing growth hormone

Lactotrophs, producing prolactin

Corticotrophs, producing ACTH

Thyrotrophs, producing thyroid-stimulating hormone (TSH)

Gonadotrophs, producing follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

Cells that do not react with antibodies to any of the previously mentioned hormones are called null cells and represent either undifferentiated stem cells or exhausted and nonfunctioning cells. Some nonfunctioning cells have prominent eosinophilic cytoplasm and contain numerous mitochondria. These cells are called oncocytes. The posterior lobe of the pituitary is composed of axonal processes of hypothalamic neurons and does not contain hormone-producing cells.

11 Are the pituitary tumors composed of the same cells as the normal pituitary?

Most pituitary tumors are monoclonal and are composed of a single cell type corresponding to one of the six cell types found in the normal anterior lobe of the pituitary. Axons of the posterior pituitary do not form tumors.

12 What is the most common tumor of the pituitary?

Most pituitary tumors (>95%) are benign and classified as adenomas. Most adenomas are composed of a single cell type and secrete only one hormone. Prolactinomas, which account for approximately 30% of all pituitary tumors, are the most common pituitary neoplasm.

13 Are all pituitary tumors hormonally active?

Approximately 80% of all pituitary tumors are hormonally active. In the remaining 20% of cases, the pituitary tumors are composed of hormonally inactive cells, which may compress the normal gland and cause hypopituitarism. Small clinically undiagnosed pituitary tumors may be found accidentally in 20% of routine adult autopsies.

14 What is the most common cause of hyperpituitarism?

Pituitary adenomas are the most common cause of pituitary hyperfunction syndromes. Carcinomas and hyperplasias account for no more than 5% or 6% of all cases.

16 What are the main clinical features of hyperprolactinemia?

In women of reproductive age, hyperprolactinemia causes amenorrhea and galactorrhea. In men, the symptoms are more subtle and may include loss of libido and infertility.

17 Why is hyperprolactinemia usually treated with bromocriptine?

In normal circumstances, pituitary lactotrophs are inhibited by dopamine and therefore do not secrete prolactin. Many cases of hyperprolactinemia are related to a loss of this dopaminergic inhibition. Bromocriptine, a dopamine agonist, will inhibit prolactin secretion and cause regression of lactotroph hyperplasia and even microscopic prolactinomas. Larger tumors that do not respond must be removed surgically, usually by a transethmoidal approach.

18 What are the clinical manifestations of growth hormone-secreting tumors?

In growing children and adolescents, growth hormone–secreting adenomas cause gigantism, whereas in adults, these tumors cause acromegaly.

19 What are the features of acromegaly?

The most prominent findings are the marked enlargement of hands and feet, nose, and jaws (“acra,” i.e., protruding terminal parts). These externally visible changes are accompanied by internal organomegaly and metabolic disorders (diabetes, hypertension, etc.). The most common findings are illustrated in Fig. 18-3.

Figure 18-3 Acromegaly.

(From Underwood JCE: General and Systemic Pathology, 3rd ed. Edinburgh, Churchill Livingstone, 2000, p. 413.)

20 What is Cushing disease?

Cushing disease is hypercortisolism caused by an ACTH-secreting tumor. Because the ACTH molecule contains a fragment that has a melanocyte-stimulating function, the disease is associated with hyperpigmentation of the skin.

21 How do gonadotroph adenomas present clinically?

These tumors do not produce distinct clinical syndromes and are usually diagnosed only after they have attained a size that will cause a mass effect. Menstrual abnormalities, infertility, and various nonspecific hormonal changes are found in some patients.

22 What are null cell adenomas?

Null cell adenomas are hormonally inactive tumors recognized by their mass effect. Large tumors may cause hypopituitarism.

23 What is the anatomic substrate of hypopituitarism?

Clinical signs of hypopituitarism appear after a loss of 75% or more of the anterior pituitary.

24 What are the most common causes of hypopituitarism?

Tumors, especially nonfunctioning adenomas and primary or metastatic carcinomas

Stalk lesion due to surgery, trauma, or neoplasms of the brain

It is worth remembering that pituitary insufficiency may be caused by several pathologic processes that all begin with the letter “i”:

Invasion of the pituitary, pituitary stalk, or the hypothalamic nuclei by tumors

Injury (e.g., head trauma with basal fractures or brain surgery)

Infarction (e.g., postpartum pituitary necrosis known as Sheehan syndrome)

Irradiation (for brain tumors or base of the skull and ear, nose, and throat tumors)

Immune diseases (e.g., sarcoidosis and autoimmune hypophysitis)

Infection (e.g., basal meningitis and tuberculosis)

Inborn errors of metabolism (mostly childhood diseases; in adults the most common is iron deposition in hemochromatosis)

Idiopathic (after all other causes have been excluded)

25 What is Sheehan syndrome?

Sheehan syndrome is also known as postpartum pituitary necrosis. Previously it was the most common form of ischemic necrosis of the pituitary, but it is rare today. It develops due to massive blood loss at the time of delivery, causing hypoperfusion of the pituitary that has undergone physiologic hyperplasia during pregnancy. Symptoms include hypothyroidism, adrenal insufficiency, and amenorrhea.

26 What is the empty sella syndrome?

This term is applied to a variety of conditions in which the sella turcica appears “empty.” In primary empty sella syndrome, which rarely presents with hypopituitarism, the pituitary atrophy is related to a compression by the cerebrospinal fluid and arachnoidea that invaginate into the sella through a defect in the diaphragm. Secondary empty sella is a consequence of surgical intervention or radiation therapy.

27 What is diabetes insipidus?

Diabetes insipidus is a syndrome characterized by polyuria, polydipsia, and renal loss of water due to a deficiency of ADH. It may be caused by injury of the hypothalamus, pituitary stalk, or posterior pituitary.

28 What is the syndrome of inappropriate ADH secretion?

This syndrome, characterized by excessive renal retention of water and dilutional hyponatremia, is caused by hyperproduction of ADH. The most common causes of ADH overproduction are small cell lung cancer, chronic lung disease, and hypothalamic lesions.

29 What is craniopharyngioma?

Craniopharyngiomas are tumors originating from remnants of the Rathke pouch, the embryonic anlage of the anterior pituitary. These tumors occur in children and young adults, and they are located in the suprasellar space, causing lesions of the hypothalamus and the pituitary stalk.

THYROID

30 How does the thyroid develop?

The thyroid develops during early embryonic life from the outpouching of the pharyngeal epithelium at the base of the tongue. This epithelium proliferates and forms the thyroglossal duct, which extends caudally, finally forming the thyroid on the anterior side of the neck. The thyroglossal duct involutes normally during fetal life, but if this involution is not complete its remnants give rise to thyroglossal duct cysts.

31 What are the basic functional units of the thyroid?

Thyroid cells are arranged into functional units called follicles. Follicles are lined by cuboidal epithelium surrounding the centrally located colloid, composed of thyroglobulin.

33 What are goitrogens?

Goitrogens are substances such as propylthiourea that interfere with the synthesis of T4 and T3. In an effort to compensate for the reduced production of T4 and T3, thyroid follicles enlarge and become lined by hyperplastic epithelium. Inefficient synthesis of T3/T4 leads to an accumulation of colloid in follicles. These dilatated follicles cause enlargement of the thyroid known as goiter or struma.

34 Which thyroid cells produce calcitonin?

Calcitonin is a hormone that stimulates the uptake of serum calcium into the bones. It is produced by parafollicular or C cells of the thyroid.

35 What is the most common cause of hyperthyroidism?

Graves disease, an autoimmune disease associated with diffuse enlargement of the thyroid, accounts for 85% of the cases of hyperthyroidism.

36 Can multinodular goiter cause hyperthyroidism?

Yes. Some goiters contain hyperfunctioning thyroid cells, which form nodules detectable by radioactive iodine scanning (“hot nodules”). Solitary hyperfunctioning nodules in an otherwise normal thyroid represent benign tumors (adenomas) that account for a small percentage of hyperthyroidisms.

38 Is exophthalmos found in all forms of hyperthyroidism?

No. Exophthalmos is found only in patients with Graves disease. It is associated with lymphocytic infiltrates in the retroorbital tissues. External eye muscles are particularly affected and appear swollen. This enlargement of the retroorbital tissue and orbital muscles leads to proptosis (anterior displacement of the eyeball). The weakness of eye muscles results in functional disturbances such as diplopia and inability to read. During physical examination, these patients show conjunctival congestion and palpebral symptoms (“lid lag” and “lid retraction”).

39 Which laboratory tests are most useful for diagnosing hyperthyroidism?

The most useful tests are based on the measurements of TSH, T4, and T3 (total and free form). Increased serum TBG (in pregnancy) or decreased TBG (in cirrhosis) may influence the concentration of T3/T4 in blood. Radioactive iodine uptake is followed by a thyroid scan to determine whether the entire thyroid is hyperfunctioning or whether the disease is caused by a hyperfunctioning nodule.

41 What is the most common cause of hypothyroidism?

Hashimoto (autoimmune) thyroiditis is the most common cause of hypothyroidism in the United States, as well as in other developed countries that use iodized salt. In some underdeveloped mountainous regions of Asia (Himalayas) or South America (Andes), iodine deficiency is a significant cause of goiter, which may be accompanied by hypothyroidism.

42 What is the cause of cretinism?

Cretinism is a term used for hypothyroidism of infancy and early childhood. Previously, it was endemic in iodine-deficient areas. Today it is rare in the United States and is most often caused by congenital agenesis of the thyroid or inborn errors of iodine metabolism and thyroid hormone synthesis.

43 What are the clinical features of cretinism?

Hypothyroidism of infancy and early childhood retards the somatic growth and affects the development of the central nervous system. These children have short stature and are mentally retarded. Their faces have coarse features and a protruding tongue.

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