The Thyroid

The thyroid gland, which is the largest endocrine organ, secretes primarily thyroid hormones that play a critical role in the normal growth and development of the maturing human. In the adult, thyroid hormones maintain metabolic stability by regulating oxygen requirements, body weight, and intermediary metabolism. Thyroid function is under hypothalamic-pituitary control, and thus, like the gonads and adrenal cortex, it serves as a classical model of endocrine physiology. In addition, the physiological effects of thyroid hormones are regulated by complex extrathyroidal mechanisms resulting from the peripheral metabolism of the hormones, mechanisms that are not under hypothalamic-pituitary regulation. Thyroid function abnormalities are very prevalent, especially in females and in certain geographic areas, and are often a result of autoimmunity or iodine deficiency. The thyroid originates from two distinct parts of the embryonic endoderm: • The follicular structures arise from a midline thickening of the anterior pharyngeal floor (the base of the tongue), adjacent to the differentiating heart. This thyroid diverticulum first expands ventrally while still attached to the pharyngeal floor by its stalk (thyroglossal duct), and then expands laterally, leading to the characteristic bilobed structure. As the developing heart descends, the thyroid gets pulled into its final position, a process that leads to the rapid stretch and degeneration of the thyroglossal duct. • The parafollicular cells are derived from the ultimobranchial bodies (originating from the neural crest) but ultimately are surrounded by the medial thyroid. The parafollicular cells represents <10 % of the adult thyroid gland. The thyroid completes its structural development by 9 weeks of gestation, the first endocrine organ to assume its definitive form during organogenesis; yet full functional maturation and integration with the hypothalamic-pituitary axis continues throughout gestation. Abnormal thyroid development can lead to persistence of the thyroglossal duct, presence of ectopic thyroid tissue (lingual thyroid, lateral aberrant thyroid), and malposition (thoracic goiter), all of which can remain clinically silent or present later in life as diagnostic challenges. The shape of the human thyroid resembles that of a butterfly.

Female Reproductive Function

The production of germ cells is essential for the continuation of a species. In the female this function is accomplished by the ovaries. In addition, the ovaries secrete steroids and nonsteroidal hormones that not only regulate the secretion of anterior pituitary hormones but also act on various target organs, including the ovaries themselves, the uterus, fallopian tubes, vagina, mammary gland, and bone. Morphologically, the ovary has three regions: an outer cortex that contains the oocytes and represents most of the mass of the ovary; the inner medulla, formed by stromal cells and cells with steroid-producing characteristics; and the hilum, which, in addition to serving as the point of entry of the nerves and blood vessels, represents the attachment region of the gland to the mesovarium. The cortex, which is enveloped by the germinal epithelium, contains the follicles, which are the functional units of the ovary. They are present in different states of development or degeneration (atresia), each enclosing an oocyte. In addition to the oocyte, ovarian follicles have two other cellular components: granulosa cells, which surround the oocyte, and thecal cells, which are separated from the granulosa cells by a basal membrane and are arranged in concentric layers around this membrane. The follicles are embedded in the stroma, which is composed of supportive connective cells similar to that of other tissues, interstitial secretory cells, and neurovascular elements. The medulla has a heterogeneous population of cells, some of which are morphologically similar to the Leydig cells in the testes. These cells predominate in the ovarian hilum; their neoplastic transformation results in excess androgen production. The ovary produces both steroids and peptidergic hormones. Whereas the steroids are synthesized in both interstitial and follicular cells, peptidergic hormones are primarily produced in follicular cells and, after ovulation, by cells of the corpus luteum. The initial precursor for steroid biosynthesis is cholesterol, which derives from animal fats of the diet or from local synthesis.

Mechanisms of Hormone Action

The capacity of a cell to respond to a particular hormone depends on the presence of cellular receptors specific for that hormone. After binding hormone, the receptor is biochemically and structurally altered, resulting in its activation; the activated receptor then mediates all of the actions of the hormone on the cell. The steroid and thyroid hormones as well as retinoids and 1,25-dihydroxyvitamin D3 diffuse freely through the lipophilic plasma membrane of the cell and interact with receptors that are primarily within the nucleus. On activation, the receptors alter the transcription of specific genes, resulting in changes in the levels of specific messenger RNAs (mRNAs), which are in turn translated into proteins. Hormones that are water soluble, such as the peptide and polypeptide hormones, catecholamines, and other neurotransmitters, as well as the relatively hydrophobic prostaglandins, interact with receptors in the plasma membrane. After hormone binding, the activated membrane receptors initiate signal transduction cascades that result in changes in enzyme activities and alterations in gene expression. In this chapter, the properties of various classes of receptors that are localized within the plasma membranes of target cells and the signal transduction mechanisms that mediate interactions with their ligands will first be addressed. This will be followed by consideration of the structural properties of the nuclear hormone receptors, the events that result in their activation, and the mechanisms whereby the activated nuclear receptors alter the expression of specific genes. Finally, a number of endocrine disorders that are caused by alterations in the number and/or function of plasma membranes and nuclear receptors will be reviewed. The function of a receptor is to recognize a particular hormone among all the molecules in the environment of the cell at a given time and, after binding the hormone, to transmit a signal that ultimately results in a biological response. Hormones are normally present in the circulation in extremely low concentrations, ranging from 10 –9 to 10 –11 M.

The Adrenal Glands

The basic function of the adrenal glands is to protect the organism against acute and chronic stress, a concept popularized as the fight-or-flight response for the medulla and as the alarm reaction for the cortex. The steroid hormones of the cortex and the catecholamines of the medulla probably developed as protection against immediate stress or injury and more prolonged deprivation of food and water. In acute stress, catecholamines mobilize glucose and fatty acids for energy and prepare the heart, lungs, and muscles for action, while glucocorticoids protect against overreactions from the body’s responses to stress. In the more chronic stress of food and fluid deprivation, adrenocortical steroid hormones stimulate gluconeogenesis to maintain the supply of glucose and increase sodium reabsorption to maintain body fluid volume. Based on the widespread effects of its secreted products in multiple tissues, adrenal dysfunction is associated with protean manifestations. Diseases associated with adrenocortical hypofunction are relatively rare, while those associated with adrenocortical hyperfunction are slightly more common. However, both of these conditions are life threatening if untreated, and a high index of suspicion must therefore be maintained. Subtle increases in cortisol secretion or tissue sensitivity to glucocorticoids may be involved in many of the devastating effects of chronic stress, including visceral obesity, hypertension, diabetes mellitus, dyslipidemia, infertility, and depression. Moreover, exogenous glucocorticoids are widely used to treat numerous diseases and, when used in supraphysiological doses, can induce all of the manifestations of glucocorticoid excess. Perhaps because the adrenal medulla accounts for only 10 % of total sympathetic nervous activation, we can live quite well without it, and syndromes due to hypofunction are not clinically significant. However, conditions of excess catecholamine output due to tumors called pheochromocytomas are a rare but potentially life-threatening cause of secondary hypertension.

The Anterior Pituitary and Hypothalamus

The hypothalamic-pituitary complex represents the core of the neuroendocrine system. The hypothalamus is composed of a diversity of neurosecretory cells arranged in groups, which secrete their products either into the portal blood system that connects the hypothalamus to the adenohypophysis (see later) or directly into the general circulation after storage in the neurohypophysis (see Chapter 6). Because of the nature of their actions, the hypothalamic hormones are classified as releasing or inhibiting hormones. The hypothalamic hormones delivered to the portal blood system are transported to the adenohypophysis, where they stimulate or inhibit the synthesis and secretion of different trophic hormones. In turn, these hormones regulate gonadal, thyroid, and adrenal function, in addition to lactation, bodily growth, and somatic development. No attempt will be made in this chapter to cover the actions of the different pituitary trophic hormones on their target glands, because they are discussed in detail in other chapters. An exception to this is growth hormone (GH). Although Chapter 11 considers several aspects of the control and actions of GH, a broader discussion of its physiological actions will be presented here because GH is the only anterior pituitary hormone that does not have a clear-cut target gland. The pituitary gland has two parts: the neurohypophysis, of neural origin (see Chapter 6), and the adenohypophysis, of ectodermal origin. In embryonic development, an evagination from the roof of the pharynx pushes dorsally to reach a ventrally directed evagination from the base of the diencephalon. The dorsally projecting evagination, known as Rathke’s pouch , forms the adenohypophysis, whereas the ventrally directed evagination of neural tissue forms the neurohypophysis. The neurohypophysis has three parts: the median eminence, the infundibular stem, and the neural lobe itself. The median eminence represents the intrahypothalamic portion and lies just ventral to the floor of the third ventricle protruding slightly in the midline. The main part of the neurohypophysis, the neural lobe, is connected to the median eminence by the infundibular stem.

Assessment of Endocrine Function

This chapter describes the various methods used for quantifying concentrations of circulating hormones and thus assessing endocrine function. The paradigm of feedback regulation (for example, of the hypothalamic-pituitary-target gland axis) is central to this assessment of endocrine status. Any disruption in such an axis can cause alterations in trophic and target hormone pairs. High concentration of a target gland hormone coupled with low concentration of the corresponding trophic hormone (e.g., pituitary hormone) suggests autonomous secretion by the target endocrine organ, as is typical in primary hyperthyroidism, e.g., high thyroxine (T4), suppressed thyroid stimulating hormone (TSH). Elevated concentrations of both members of a hormone pair usually indicate autonomous secretion of the trophic hormone, either from the normal site or from a tumor in an “ectopic” (extraglandular) location. For example, excess cortisol production driven by a high plasma adrenocorticotropic hormone (ACTH) level may be due to the secretion of pituitary ACTH or secretion of ACTH by lung tumors. Alternatively, the combined elevation of trophic and target endocrine gland hormones can result from resistance to the action of the target endocrine gland hormone e.g., elevated luteinizing hormone (LH) and testosterone in androgen resistance. Autonomous hypersecretion of the trophic hormone typically results in clinical evidence of target gland hormone excess, whereas resistance to the target gland hormone leads to manifestations of hormone deficiency. Hormones circulating in the plasma were first detected by in vivo bioassays, in which plasma or extracts of plasma were injected into animals and biological responses were measured. Unfortunately, most in vivo bioassays lack the precision, sensitivity, and specificity required to measure the low concentrations of many hormones in plasma, and the assays are cumbersome and impractical for routine use in clinical chemistry laboratories. Great progress in measuring plasma hormone concentrations came with the development of radioimmunoassays (RIAs) in the late 1950s. An unknown concentration of hormone in plasma is estimated by allowing competition with a labeled hormone or analog for specific binding sites on an antibody.

Genes and Hormones

Much of the knowledge presented in the following chapters has been gained using molecular genetic techniques to analyze the structure, synthesis, regulation, and effects of hormones. This chapter provides an overview of some of the relevant techniques and associated concepts. To allow the reader to understand older experiments, we have tried to include techniques that are now of mainly historical interest as well as current concepts. Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) consist of nucleotides . A nucleotide consists of a base , a sugar moiety (either deoxyribose or ribose), and a phosphate group. The sugars and phosphates alternate in the backbone of a nucleic acid strand. In general, there are four possible bases. In DNA, these are adenine ( A ), cytosine ( C ), guanine ( G ), and thymine ( T ). Adenine and guanine are purines , whereas cytosine and thymine are pyrimidines . The corresponding nucleotides are adenosine , cytidine , guanosine , and thymidine. In RNA, uracil (uridine) is substituted for thymine (thymidine). DNA is double stranded. Each strand has a direction because the deoxyribose molecules forming the backbone are asymmetrical, with the phosphate bonds linking each two sugar molecules going from the 3’ position of one to the 5’ position of the next. Thus, the 5’ position of a sugar molecule is free at one end (the 5’ end) of the strand, and the 3’ position is free at the other. The two strands of a DNA molecule run in opposite directions, so that the 5’ end of one strand is opposed to the 3’ end of the complementary strand. The DNA strands interact with each other through complementary (Watson-Crick) base pairing , in which A and T, or C and G, are paired through hydrogen bonds. Thus, the sequence of one DNA strand unambiguously determines the sequence of the complementary strand during DNA replication. The length of a DNA segment is typically given in bases or nucleotides (nt) or, if double stranded, base pairs (bp).

Glucose, Lipid, and Protein Metabolism

The maintenance of life requires a constant supply of substrate for the generation of energy and preservation of the structure of cells and tissues. The process in principle is simple, yet the individual metabolic pathways and the regulation of substrate fluxes through these pathways can be complex. Energy is derived when fuel substrates are oxidized to carbon dioxide and water in the presence of oxygen, generating adenosine triphosphate (ATP). A portion of the ingested foodstuff is also utilized, either directly or after transformation into other substrates, to repair and replace cell membranes, structural proteins, and organelles. The remainder is stored as potential energy in the form of glycogen or fat. Under normal circumstances, each individual remains in a near-steady state where weight and appearance are stable over prolonged periods. In the short term, fuel metabolism changes dramatically several times a day during alternating periods of feeding and fasting. An anabolic phase begins with food ingestion and lasts for several hours. Energy storage occurs during this period when caloric intake exceeds caloric demands. The catabolic phase usually begins 4 to 6 hours after a meal and lasts until the person eats once again. During this phase, utilization shifts from exogenous to endogenous fuels, a change heralded by the mobilization of substrate stored in liver, muscle, and adipose tissue. Both anabolic and catabolic phases are characterized by specific biochemical processes regulated by distinct hormonal profiles. In the anabolic phase that follows ingestion of a mixed meal, substrate flux is directed from the intestine through the liver to storage and utilization sites. Glucose, triglyceride, and amino acid concentrations increase in plasma, whereas those of fatty acids, ketones (acetoacetic and β -hydroxy-butyric acids), and glycerol decrease. Both glycogen and protein synthesis begin in liver and muscle, while fatty acid synthesis and triglyceride esterification are stimulated in hepatocytes and adipose tissue. In the catabolic phase, the biochemical activities are reversed and the flux of fuel is directed from storage depots to liver and other utilization sites.

Calcium Homeostasis

Ionized calcium plays a pivotal role in many physiological and biochemical processes, including the contraction of muscles, the clotting of blood, and impulse conduction in the heart and nervous system. Moreover, it acts as a secondary messenger within the cell to initiate other cascades important for cell signaling and both exocrine and endocrine secretion. The major storage sites for calcium in the body are the teeth and skeleton. These hard tissues, which contain 99 % of the body’s calcium (approximately 1 kg), provide the structure necessary for mastication, locomotion, and protection of internal organs. In the blood, calcium is found in three forms — ionized (50%), protein-bound (40 %), and soluble complexes (10 %). Unlike the other two forms of calcium, the protein-bound fraction, which is primarily bound to albumin, is not filtered by the kidney. In normal individuals, the range of serum total calcium is 8.5 to 10.3 mg/dl. In a given individual, however, the diurnal variation of serum calcium is limited to 0.3 mg/dl. This chapter reviews calcium homeostasis in the extracellular fluid, the integrated response to calcium stressors, and disorders of calcium metabolism. The bone, kidneys, and intestines are the most important calcium-transporting tissues and play an important role in calcium homeostasis. These three corners of the calcium homeostasis triangle are discussed individuallyin the sections that follow. The bone is a dynamic tissue that is constantly changing. From birth until the completion of puberty, bone lengthens and changes shape by a process called modeling. In the adult skeleton, remodeling is the process used to repair damaged areas, to strengthen sites of stress or injury, and to remove unnecessary bone from sparsely used skeletal sites. The entire skeleton is demolished and refabricated by this process within 10 years. There are two main types of bone that remodel at different rates. Cortical bone, which makes up 80 % of the bone mass, is highly calcified, dense tissue found mainly in the appendicular skeleton such as the arms and legs.

Growth Regulation

While multiple hormones influence somatic growth, the main regulator of postnatal growth is growth hormone. Growth hormone (GH) is secreted in a pulsatile manner from the anterior pituitary primarily as a 22-kilodalton molecule (although other forms may be found). The development of the pituitary gland as well as GH gene expression is regulated by the multiple pituitary transcription factors listed in Table11-1. The Pit-1 and Prop-1 genes encode proteins that are often mutated or deleted in cases of congenital hypopituitarism. Under normal waking conditions, GH levels are often low or undetectable, but several times during the day, and particularly at night during stage 3 of sleep, surges of GH secretion occur. The pulsatile pattern characteristic of GH secretion largely reflects the interaction of multiple regulators, including two hypothalamic regulatory peptides: GH-releasing hormone (GHRH), which stimulates GH secretion, and somatostatin (somatotropin release–inhibiting factor [SRIF]), which inhibits GH secretion. Multiple neurotransmitters and neuropeptides are involved in regulation of release of these hypothalamic factors, including, but not limited to, serotonin, histamine, norepinephrine, dopamine, acetylcholine, γ -aminobutyric acid (GABA), thyroid-releasing hormone, vasoactive intestinal peptide, gastrin, neurotensin, substance P, calcitonin, neuropeptide Y, vasopressin, corticotropinreleasing hormone, and galanin. Many factors influence GH secretion; notably, glucose that inhibits, and certain amino acids and Ghrelin that stimulate GH secretion. GH secretion is also impacted by a variety of nonpeptide hormones, including androgens, estrogens, thyroxine, and glucocorticoids. The precise mechanisms by which these hormones regulate GH secretion are complex, potentially involving actions at both the hypothalamic and pituitary levels. Exogenous physiological and pharmacological factors are known to stimulate GH secretion. Some of these agents, including clonidine, L-dopa, and exercise, are used in GH stimulation tests. In plasma, the majority of GH is bound with high specificity and affinity, but with relatively low capacity to a carrier protein termed GH binding protein (GHBP). The GHBP is a cleavage product of the extracellular domain of the GH receptor.