1 Introduction to the Endocrine System OBJECTIVES 1. List the main endocrine glands of the body. 4. Explain the significance of hormone binding to plasma 2. List the chemical nature of the major hormones. proteins. 3. Describe how the chemical nature influences hormone 5. Describe the major signal transduction pathways, and synthesis, storage, secretion, transport, clearance, their mechanism for termination, for different classes mechanism of action, and appropriate route of exoge- of hormones and provide a specific example of each. nous hormone administration. Endocrine glands secrete chemical messengers, called hor- hydroxylations of vitamin D in hepatocytes and renal mones (Box 1.1), into the extracellular fluid in a highly tubular cells. regulated manner. Secreted hormones gain access to the cir- Numerous extracellular messengers, including prosta- culation, often via fenestrated capillaries, and regulate target glandins, growth factors, neurotransmitters, and cytokines, organs throughout the body. The endocrine system is com- also regulate cellular function. However, these messengers posed of the pituitary gland, the thyroid gland, parathy- act predominantly within the context of a microenviron- roid glands, and adrenal glands (Fig. 1.1). The endocrine ment in an autocrine or paracrine manner, and thus are system also includes the ovary and testis, which carry out a discussed only to a limited extent where needed. gametogenic function that is absolutely dependent on their To function, hormones must bind to specific recep- endogenous endocrine function. In addition to dedicated tors expressed by specifictarget cell types within target endocrine glands, endocrine cells reside as a minor compo- organs. Hormones are also referred to as ligands, in the nent (in terms of mass) in other organs, either as groups of context of ligand receptor binding, and as agonists, in that cells (the islets of Langerhans in the pancreas) or as indi- their binding to the receptor is transduced into a cellular vidual cells spread throughout several glands, including the response. Receptor antagonists typically bind to a receptor gastrointestinal (GI) tract, kidney, heart, adipose tissue, and lock it in an inactive state, unable to induce a cellular and liver. In addition, there are several types of hypotha- response. Drugs that bind to and alter the activity of ste- lamic neuroendocrine neurons that produce hormones. roid hormone receptors are referred to as selective receptor The placenta serves as a transitory exchange organ, but also modulators. For example, Tamoxifen is a mixed estrogen functions as an important endocrine structure of pregnancy. receptor agonist/antagonist, and thus is referred to as a The endocrine system also encompasses a range of spe- “selective estrogen receptor modulator” or SERM. Loss cific enzymes, either cell-associated or circulating, that per- or inactivation of a receptor leads to hormonal resistance. form the function of peripheral conversion of hormonal Constitutive activation of a receptor leads to unregulated, precursors (see Box 1.1). For example, angiotensinogen hormone-independent activation of cellular processes. from the liver is converted in the circulation to angiotensin The widespread delivery of hormones in the blood I by the renal-derived enzyme renin, followed by conver- makes the endocrine system ideal for the functional coor- sion to the active hormone angiotensin II by the trans- dination of multiple organs and cell types in the following membrane ectoenzyme angiotensin I–converting enzyme contexts: (ACE) that is enriched in the endothelia of the lungs (see 1. Allowing normal development and growth of the Chapter 7). Another example of peripheral conversion of a organism precursor to an active hormone involves the two sequential 2. Maintaining internal homeostasis 1 2 CHAPTER 1 Introduction to the Endocrine System BOX 1.1 A List of Most Hormones and Their Sites of Production Hormones Synthesized and Secreted by Dedicated Dopamine Endocrine Glands Pituitary Gland Brain (Pineal Gland) Growth hormone (GH) Melatonin Prolactin Adrenocorticotropic hormone (ACTH) Heart Thyroid-stimulating hormone (TSH) Atrial natriuretic peptide (ANP) Follicle-stimulating hormone (FSH) Kidney Luteinizing hormone (LH) Erythropoietin Thyroid Gland Adipose Tissue Tetraiodothyronine (T ; thyroxine) 4 Leptin Triiodothyronine (T ) 3 Adiponectin Calcitonin Stomach Parathyroid Glands Gastrin Parathyroid hormone (PTH) Somatostatin Islets of Langerhans (Endocrine Pancreas) Ghrelin Insulin Intestines Glucagon Secretin Somatostatin Cholecystokinin Adrenal Gland Glucagon-like peptide-1 (GLP-1) Epinephrine Glucagon-like peptide-2 (GLP-2) Norepinephrine Glucose-dependent insulinotropic peptide (GIP; gastrin Cortisol inhibitory peptide) Aldosterone Motilin Dehydroepiandrosterone sulfate (DHEAS) Liver Hormones Synthesized by Gonads Insulin-like growth factor-I (IGF-I) Ovaries Hormones Produced to a Significant Degree by Estradiol-17 β Peripheral Conversion Progesterone Lungs Inhibin Angiotensin II Testes Testosterone Kidney Antimüllerian hormone (AMH) 1α,25-dihydroxyvitamin D Inhibin Adipose, Mammary Glands, Other Organs Hormones Synthesized in Organs with a Primary Estradiol-17β Function Other Than Endocrine Brain (Hypothalamus) Liver, Other Organs Antidiuretic hormone (ADH; vasopressin) Testosterone Oxytocin Corticotropin-releasing hormone (CRH) Genital Skin, Prostate, Sebaceous Gland, Other Organs Thyrotropin-releasing hormone 5-Dihydrotestosterone (DHT) Gonadotropin-releasing hormone (GnRH) Growth hormone–releasing hormone (GHRH) Many Organs Somatostatin T3 CHAPTER 1 Introduction to the Endocrine System 3 Hypothalamus Pituitary gland Thyroid gland Parathyroid glands Adrenal glands Pancreas Ovaries Testes Fig. 1.1 Major glands of the endocrine sys- tem. (From Koeppen BM, Stanton BA, ed- itors: Berne and Levy Physiology, 6th ed., Philadelphia, 2010, Mosby.) 3. Regulating the onset of reproductive maturity at BOX 1.2 Characteristics of Protein/ puberty and the function of the reproductive system in Peptide Hormones the adult In the adult, endocrine organs produce and secrete • Synthesized as prehormones or preprohormones their hormones in response to feedback control systems • Stored in membrane-bound secretory vesicles (some- that are tuned to set-points, or set ranges, of the levels times called secretory granules) of circulating hormones. These set-points are genetically • Regulated at the level of secretion (regulated exocy- determined but may be altered by age, circadian rhythms tosis) and synthesis (24-hour cycles or diurnal rhythms), seasonal cycles, the • Often circulate in blood unbound environment, stress, inflammation, and other influences. • Usually administered by injection Major forms of endocrine disease are caused by lack of • Hydrophilic and signal through transmembrane receptors hormone (e.g., hypothyroidism), excess of hormone (e.g., hyperparathyroidism) or dysfunction of receptor (hor- monal resistance). It is important to appreciate that hor- CHEMICAL NATURE OF HORMONES mones often stimulate both the differentiated function and growth of target tissues and organs. This underlies the role Hormones are classified biochemically asproteins/peptides, of hormones in driving neoplastic transformation and can- catecholamines, steroid hormones, and iodothyronines. cer progression (i.e., the existence of hormonally respon- The chemical nature of a hormone determines the following: sive cancers). The pathogenesis of these and other forms of 1. How it is synthesized, stored, and released in a regulated endocrine disease are discussed in the subsequent chapters. manner The material in this chapter covers generalizations 2. How it is carried in the blood common to all hormones or to specific groups of hor- 3. Its biologic half-life (t1/2) and mode of clearance mones. The chemical nature of the hormones and their 4. Its cellular mechanism of action mechanisms of action are discussed. This presentation provides the generalized information necessary to cate- Proteins/Peptides gorize the hormones and to make predictions about the The protein and peptide hormones can be grouped into most likely characteristics of a given hormone. Some structurally related molecules that are encoded by gene of the exceptions to these generalizations are discussed families (Box 1.2). Protein/peptide hormones gain their later. specificity from their primary amino acid sequence, which 4 CHAPTER 1 Introduction to the Endocrine System Pre-growth hormone Signal peptidase Growth hormone A Prepro-opiomelanocortin Signal peptidase Pro-opiomelanocortin Pituitary specific prohormone convertases && ACTH Fig. 1.2 Prehormone (A) and preprohormone (B) B processing with specific examples. confers specific higher-order structures, and from post- hypothalamic neurons produce αMSH, but not ACTH. translational modifications, such as glycosylation. The ability of cells to process the same prohormone into Protein/peptide hormones are synthesized on the polyr- different peptides is due to cell type expression of prohor- ibosome as larger preprohormones. The nascent peptides mone convertases, resulting in cell-specific processing of have at their N terminus a group of 15 to 30 amino acids the prohormone. called the signal peptide, which directs the growing poly- Protein/peptide hormones are stored in the gland as peptide through the endoplasmic reticular membrane membrane-bound secretory vesicles and are released into the cisternae. The signal peptide is enzymatically