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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