Endocrine System

Endocrine System: Overview

• Endocrine system – the body’s second great controlling system which influences metabolic activities of cells by means of hormones

• Endocrine glands – pituitary, thyroid, parathyroid, adrenal, pineal, and thymus glands

• The pancreas and gonads produce both hormones and exocrine products

• The hypothalamus has both neural functions and releases hormones

• Other tissues and organs that produce hormones – adipose cells, pockets of cells in the walls of the small intestine, stomach, kidneys, and heart

Hormones

• Hormones – chemical substances secreted by cells into the extracellular fluids

• Regulate the metabolic function of other cells

• Have lag times ranging from seconds to hours

• Tend to have prolonged effects

• Are classified as amino acid-based hormones, or steroids

• Eicosanoids – biologically active lipids with local hormone–like activity

Types of Hormones

• Amino acid–based – most hormones belong to this class, including:

• Amines, thyroxine, peptide, and protein hormones

• Steroids – gonadal and adrenocoritcal hormones

• Eicosanoids – leukotrienes and prostaglandins

Hormone Action

• Hormones alter cell activity by one of two mechanisms

• Second messengers involving:

• Regulatory G proteins

• Amino acid–based hormones

• Direct gene activation involving steroid hormones

• The precise response depends on the type of the target cell

Mechanism of Hormone Action

• Hormones produce one or more of the following cellular changes:

• Alter plasma membrane permeability

• Stimulate protein synthesis

• Activate or deactivate enzyme systems

• Induce secretory activity

• Stimulate mitosis

Amino Acid–Based Hormone Action: cAMP Second Messenger

• Hormone (first messenger) binds to its receptor, which then binds to a G protein

• The G protein is then activated as it binds GTP, displacing GDP

• Activated G protein activates the effector enzyme adenylate cyclase

• Adenylate cyclase generates cAMP (second messenger ) from ATP

• cAMP activates protein kinases, which then cause cellular effects

Amino Acid–Based Hormone Action:
PIP-Calcium

• Hormone binds to the receptor and activates G protein

• G protein binds and activates a phospholipase enzyme

• Phospholipase splits the phospholipid PIP₂ into diacylglycerol (DAG) and IP₃ (both act as second messengers)

• DAG activates protein kinases; IP₃ triggers release of Ca²⁺ stores

• Ca²⁺ (third messenger) alters cellular responses

Amino Acid–Based Hormone Action:
PIP-Calcium

Steroid Hormones

• Steroid hormones and thyroid hormone diffuse easily into their target cells

• Once inside, they bind and activate a specific intracellular receptor

• The hormone-receptor complex travels to the nucleus and binds a DNA-associated receptor protein

• This interaction prompts DNA transcription, to producing mRNA

• The mRNA is translated into proteins, which bring about a cellular effect

Steroid Hormones

Hormone–Target Cell Specificity

• Hormones circulate to all tissues but only activate cells referred to as target cells

• Target cells must have specific receptors to which the hormone binds

• These receptors may be intracellular or located on the plasma membrane

• Examples of hormone activity

• ACTH receptors are only found on certain cells of the adrenal cortex

• Thyroxin receptors are found on nearly all cells of the body

Target Cell Activation

• Target cell activation depends upon three factors

• Blood levels of the hormone

• Relative number of receptors on the target cell

• The affinity of those receptors for the hormone

• Up-regulation – target cells form more receptors in response to the hormone

• Down-regulation – target cells lose receptors in response to the hormone

Hormone Concentrations in the Blood

• Concentrations of circulating hormone reflect:

• Rate of release

• Speed of inactivation and removal from the body

• Hormones are removed from the blood by:

• Degrading enzymes

• The kidneys

• Liver enzyme systems

Control of Hormone Synthesis and Release

• Blood levels of hormones:

• Are controlled by negative feedback systems

• Vary only within a narrow desirable range

• Hormones are synthesized and released in response to:

• Humoral stimuli

• Neural stimuli

• Hormonal stimuli

Humoral Stimuli

• Humoral stimuli – secretion of hormones in direct response to changing blood levels of ions and nutrients

• Example: concentration of calcium ions in the blood

• Declining blood Ca²⁺ concentration stimulates the parathyroid glands to secrete PTH (parathyroid hormone)

• PTH causes Ca²⁺ concentrations to rise and the stimulus is removed

Neural Stimuli

• Neural stimuli – nerve fibers stimulate hormone release

• Preganglionic sympathetic nervous system (SNS) fibers stimulate the adrenal medulla to secrete catecholamines

Hormonal Stimuli

• Hormonal stimuli – release of hormones in response to hormones produced by other endocrine organs

• The hypothalamic hormones stimulate the anterior pituitary

• In turn, pituitary hormones stimulate targets to secrete still more hormones

Nervous System Modulation

• The nervous system modifies the stimulation of endocrine glands and their negative feedback mechanisms

• The nervous system can override normal endocrine controls

• For example, control of blood glucose levels

• Normally the endocrine system maintains blood glucose

• Under stress, the body needs more glucose

• The hypothalamus and the sympathetic nervous system are activated to supply ample glucose

Location of the Major Endocrine Glands

• The major endocrine glands include:

• Pineal gland, hypothalamus, and pituitary

• Thyroid, parathyroid, and thymus

• Adrenal glands and pancreas

• Gonads – male testes and female ovaries

Major Endocrine Organs: Pituitary (Hypophysis)

• Pituitary gland – two-lobed organ that secretes nine major hormones

• Neurohypophysis – posterior lobe (neural tissue) and the infundibulum

• Receives, stores, and releases hormones from the hypothalamus

• Adenohypophysis – anterior lobe, made up of glandular tissue

• Synthesizes and secretes a number of hormones

Pituitary-Hypothalamic Relationships: Posterior Lobe

• Posterior lobe – a downgrowth of hypothalamic neural tissue

• Has a neural connection with the hypothalamus (hypothalamic-hypophyseal tract)

• Nuclei of the hypothalamus synthesize oxytocin and antidiuretic hormone (ADH)

• These hormones are transported to the posterior pituitary

Pituitary-Hypothalamic Relationships: Anterior Lobe

• The anterior lobe of the pituitary is an outpocketing of the oral mucosa

• There is no direct neural contact with the hypothalamus

• There is a vascular connection, the hypophyseal portal system, consisting of:

• The primary capillary plexus

• The hypophyseal portal veins

Adenohypophyseal Hormones

• The six hormones of the adenohypophysis:

• Are abbreviated as GH, TSH, ACTH, FSH, LH, and PRL

• Regulate the activity of other endocrine glands

• In addition, pro-opiomelanocortin (POMC):

• Has been isolated from the pituitary

• Is enzymatically split into ACTH, opiates, and MSH

Activity of the Adenohypophysis

• The hypothalamus sends chemical stimulus to the anterior pituitary

• Releasing hormones stimulate the synthesis and release of hormones

• Inhibiting hormones shut off the synthesis and release of hormones

• The tropic hormones that are released are:

• Thyroid-stimulating hormone (TSH)

• Adrenocorticotropic hormone (ACTH)

• Follicle-stimulating hormone (FSH)

• Luteinizing hormone (LH)

Growth Hormone (GH)

• Produced by somatotropic cells of the anterior lobe that:

• Stimulate most cells, but target bone and skeletal muscle

• Promote protein synthesis and encourage the use of fats for fuel

• Most effects are mediated indirectly by somatomedins

• Antagonistic hypothalamic hormones regulate GH

• Growth hormone–releasing hormone (GHRH) stimulates GH release

• Growth hormone–inhibiting hormone (GHIH) inhibits GH release

Metabolic Action of Growth Hormone

• GH stimulates liver, skeletal muscle, bone, and cartilage to produce insulin-like growth factors

• Direct action promotes lipolysis and inhibits glucose uptake

Thyroid Stimulating Hormone (Thyrotropin)

• Tropic hormone that stimulates the normal development and secretory activity of the thyroid gland

• Triggered by hypothalamic peptide thyrotropin-releasing hormone (TRH)

• Rising blood levels of thyroid hormones act on the pituitary and hypothalamus to block the release of TSH

Adrenocorticotropic Hormone (Corticotropin)

• Stimulates the adrenal cortex to release corticosteroids

• Triggered by hypothalamic corticotropin-releasing hormone (CRH) in a daily rhythm

• Internal and external factors such as fever, hypoglycemia, and stressors can trigger the release of CRH

Gonadotropins

• Gonadotropins – follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

• Regulate the function of the ovaries and testes

• FSH stimulates gamete (eggs or sperm) production

• Absent from the blood in prepubertal boys and girls

• Triggered by the hypothalamic gonadotropin-releasing hormone (GnRH) during and after puberty

Functions of Gonadotropins

• In females

• LH works with FSH to cause maturation of the ovarian follicle

• LH works alone to trigger ovulation (expulsion of the egg from the follicle)

• LH promotes synthesis and release of estrogens and progesterone

• In males

• LH stimulates interstitial cells of the testes to produce testosterone

• LH is also referred to as interstitial cell-stimulating hormone (ICSH)

Prolactin (PRL)

• In females, stimulates milk production by the breasts

• Triggered by the hypothalamic prolactin-releasing hormone (PRH)

• Inhibited by prolactin-inhibiting hormone (PIH)

• Blood levels rise toward the end of pregnancy

• Suckling stimulates PRH release and encourages continued milk production

The Posterior Pituitary and Hypothalamic Hormones

• Posterior pituitary – made of axons of hypothalamic neurons, stores antidiuretic hormone (ADH) and oxytocin

• ADH and oxytocin are synthesized in the hypothalamus

• ADH influences water balance

• Oxytocin stimulates smooth muscle contraction in breasts and uterus

• Both use PIP second-messenger mechanisms

Oxytocin

• Oxytocin is a strong stimulant of uterine contraction

• Regulated by a positive feedback mechanism to oxytocin in the blood

• This leads to increased intensity of uterine contractions, ending in birth

• Oxytocin triggers milk ejection (“letdown” reflex) in women producing milk

• Synthetic and natural oxytocic drugs are used to induce or hasten labor

• Plays a role in sexual arousal and satisfaction in males and nonlactating females

Antidiuretic Hormone (ADH)

• ADH helps to avoid dehydration or water overload

• Prevents urine formation

• Osmoreceptors monitor the solute concentration of the blood

• With high solutes, ADH is synthesized and released, thus preserving water

• With low solutes, ADH is not released, thus causing water loss from the body

• Alcohol inhibits ADH release and causes copious urine output

Thyroid Gland

• The largest endocrine gland, located in the anterior neck, consists of two lateral lobes connected by a median tissue mass called the isthmus

• Composed of follicles that produce the glycoprotein thyroglobulin

Thyroid Gland

• Colloid (thyroglobulin + iodine) fills the lumen of the follicles and is the precursor of thyroid hormone

• Other endocrine cells, the parafollicular cells, produce the hormone calcitonin

Thyroid Hormone (TH)

• Thyroid hormone – the body’s major metabolic hormone

• Consists of two closely-related iodine-containing compounds

• T₄ – thyroxine; has two tyrosine molecules plus four bound iodine atoms

• T₃ – triiodothyronine; has two tyrosines with three bound iodine atoms

Effects of Thyroid Hormone

• TH is concerned with:

• Glucose oxidation

• Increasing metabolic rate

• Heat production

• TH plays a role in:

• Maintaining blood pressure

• Regulating tissue growth

• Developing skeletal and nervous systems

• Maturation and reproductive capabilities

Transport and Regulation of TH

• T₄ and T₃ bind to thyroxine-binding globulins (TBGs) produced by the liver

• Both bind to target receptors, but T₃ is ten times more active than T₄

• Peripheral tissues convert T₄ to T₃

• Mechanisms of activity are similar to steroids

• Regulation is by negative feedback

• Hypothalamic thyrotropin-releasing hormone (TRH) can overcome the negative feedback

Synthesis of Thyroid Hormone

• Thyroglobulin is synthesized and discharged into the lumen

• Iodides (I^–) are actively taken into the cell, oxidized to iodine (I₂), and released into the lumen

• Iodine attaches to tyrosine, mediated by peroxidase enzymes, forming T₁ (monoiodotyrosine, or MIT), and T₂ (diiodotyrosine, or DIT)

• Iodinated tyrosines link together to form T₃ and T₄

• Colloid is then endocytosed and combined with a lysosome, where T₃ and T₄ are cleaved and diffuse into the bloodstream

Calcitonin

• A peptide hormone produced by the parafollicular, or C, cells

• Lowers blood calcium levels in children

• Antagonist to parathyroid hormone (PTH)

• Calcitonin targets the skeleton, where it:

• Inhibits osteoclast activity and thus bone resorption and release of calcium from the bone matrix

• Stimulates calcium uptake and incorporation into the bone matrix

• Regulated by a humoral (calcium ion concentration in the blood) negative feedback mechanism

Parathyroid Glands

• Tiny glands embedded in the posterior aspect of the thyroid

• Cells are arranged in cords containing oxyphil and chief cells

• Chief (principal) cells secrete PTH

• PTH (parathormone) regulates calcium balance in the blood

Effects of Parathyroid Hormone

• PTH release increases Ca²⁺ in the blood as it:

• Stimulates osteoclasts to digest bone matrix

• Enhances the reabsorption of Ca²⁺ and the secretion of phosphate by the kidneys

• Increases absorption of Ca²⁺ by intestinal mucosal cells

• Rising Ca²⁺ in the blood inhibits PTH release

Adrenal (Suprarenal) Glands

• Adrenal glands – paired, pyramid-shaped organs atop the kidneys

• Structurally and functionally, they are two glands in one

• Adrenal medulla – nervous tissue that acts as part of the SNS

• Adrenal cortex – glandular tissue derived from embryonic mesoderm

Adrenal Cortex

• Synthesizes and releases steroid hormones called corticosteroids

• Different corticosteriods are produced in each of the three layers

• Zona glomerulosa – mineralocorticoids (chiefly aldosterone)

• Zona fasciculata – glucocorticoids (chiefly cortisol)

• Zona reticularis – gonadocorticoids (chiefly androgens)

Mineralocorticoids

• Regulate the electrolyte concentrations of extracellular fluids

• Aldosterone – most important mineralocorticoid

• Maintains Na⁺ balance by reducing excretion of sodium from the body

• Stimulates reabsorption of Na⁺ by the kidneys

• Aldosterone secretion is stimulated by:

• Rising blood levels of K⁺

• Low blood Na⁺

• Decreasing blood volume or pressure

The Four Mechanisms of Aldosterone Secretion

• Renin-angiotensin mechanism – kidneys release renin, which is converted into angiotensin II that in turn stimulates aldosterone release

• Plasma concentration of sodium and potassium – directly influences the zona glomerulosa cells

• ACTH – causes small increases of aldosterone during stress

• Atrial natriuretic peptide (ANP) – inhibits activity of the zona glomerulosa

Glucocorticoids (Cortisol)

• Help the body resist stress by:

• Keeping blood sugar levels relatively constant

• Maintaining blood volume and preventing water shift into tissue

• Cortisol provokes:

• Gluconeogenesis (formation of glucose from noncarbohydrates)

• Rises in blood glucose, fatty acids, and amino acids

Excessive Levels of Glucocorticoids

• Excessive levels of glucocorticoids:

• Depress cartilage and bone formation

• Inhibit inflammation

• Depress the immune system

• Promote changes in cardiovascular, neural, and gastrointestinal function

Gonadocorticoids (Sex Hormones)

• Most gonadocorticoids secreted are androgens (male sex hormones), and the most important one is testosterone

• Androgens contribute to:

• The onset of puberty

• The appearance of secondary sex characteristics

• Sex drive in females

• Androgens can be converted into estrogens after menopause

Adrenal Medulla

• Made up of chromaffin cells that secrete epinephrine and norepinephrine

• Secretion of these hormones causes:

• Blood glucose levels to rise

• Blood vessels to constrict

• The heart to beat faster

• Blood to be diverted to the brain, heart, and skeletal muscle

• Epinephrine is the more potent stimulator of the heart and metabolic activities

• Norepinephrine is more influential on peripheral vasoconstriction and blood pressure

Pancreas

• A triangular gland, which has both exocrine and endocrine cells, located behind the stomach

• Acinar cells produce an enzyme-rich juice used for digestion (exocrine product)

• Pancreatic islets (islets of Langerhans) produce hormones (endocrine products)

• The islets contain two major cell types:

• Alpha (a) cells that produce glucagon

• Beta (b) cells that produce insulin

Glucagon

• A 29-amino-acid polypeptide hormone that is a potent hyperglycemic agent

• Its major target is the liver, where it promotes:

• Glycogenolysis – the breakdown of glycogen to glucose

• Gluconeogenesis – synthesis of glucose from lactic acid and noncarbohydrates

• Releases glucose to the blood from liver cells

Insulin

• A 51-amino-acid protein consisting of two amino acid chains linked by disulfide bonds

• Synthesized as part of proinsulin and then excised by enzymes, releasing functional insulin

• Insulin:

• Lowers blood glucose levels

• Enhances transport of glucose into body cells

• Counters metabolic activity that would enhance blood glucose levels

Effects of Insulin Binding

• The insulin receptor is a tyrosine kinase enzyme

• After glucose enters a cell, insulin binding triggers enzymatic activity that:

• Catalyzes the oxidation of glucose for ATP production

• Polymerizes glucose to form glycogen

• Converts glucose to fat (particularly in adipose tissue)

Regulation of Blood Glucose Levels

• The hyperglycemic effects of glucagon and the hypoglycemic effects of insulin

Diabetes Mellitus (DM)

• Results from hyposecretion or hypoactivity of insulin

• The three cardinal signs of DM are:

• Polyuria – huge urine output

• Polydipsia – excessive thirst

• Polyphagia – excessive hunger and food consumption

• Hyperinsulinism – excessive insulin secretion, resulting in hypoglycemia

Gonads: Female

• Paired ovaries in the abdominopelvic cavity produce estrogens and progesterone

• They are responsible for:

• Maturation of the reproductive organs

• Appearance of secondary sexual characteristics

• Breast development and cyclic changes in the uterine mucosa

Gonads: Male

• Located in an extra-abdominal sac (scrotum), they produce testosterone

• Testosterone :

• Initiates maturation of male reproductive organs

• Causes appearance of secondary sexual characteristics and sex drive

• Is necessary for sperm production

• Maintains sex organs in their functional state

Pineal Gland

• Small gland hanging from the roof of the third ventricle of the brain

• Secretory product is melatonin

• Melatonin is involved with:

• Day/night cycles

• Physiological processes that show rhythmic variations

Thymus

• Lobulated gland located deep to the sternum in the thorax

• Major hormonal products are thymopoietins and thymosins

• These hormones are essential for the development of the T lymphocytes (T cells) of the immune system

Other Hormone-Producing Structures

• Heart – produces atrial natriuretic peptide (ANP), which reduces blood pressure, blood volume, and blood sodium concentration

• Gastrointestinal tract – enteroendocrine cells release local-acting digestive hormones

• Placenta – releases hormones that influence the course of pregnancy

• Kidney – secrete erythropoietin, which signals the production of red blood cells

• Skin – produces cholecalciferol, the precursor of vitamin D

• Adipose tissue – releases leptin, which is involved in the sensation of satiety

Developmental Aspects

• Hormone-producing glands arise from all three germ layers

• Endocrine glands derived from mesoderm produce steroid hormones

• Endocrine organs operate smoothly throughout life

• Most endocrine glands show structural changes with age, but hormone production may or may not be effected

• GH levels decline with age and this accounts for muscle atrophy with age

• Supplemental GH may spur muscle growth, reduce body fat, and help physique

• TH declines with age, causing lower basal metabolic rates

• PTH levels remain fairly constant with age, and lack of estrogen in women make them more vulnerable to bone-demineralizing effects of PTH

Developmental Aspects: Gonads

• Ovaries undergo significant changes with age and become unresponsive to gonadotropins

• Female hormone production declines, the ability to bear children ends, and problems associated with estrogen deficiency (e.g., osteoporosis) begin to occur

• Testosterone also diminishes with age, but effect is not usually seen until very old age