Chapter 18

The Endocrine System

 

Lecture Outline

Chapter 18
The Endocrine System

•      The nervous and endocrine systems act as a coordinated interlocking supersystem, the neuroendocrine system.

•      The endocrine system controls body activities by releasing mediator molecules called hormones.

–   hormones released into the bloodstream travel throughout the body

–   results may take hours, but last longer

•       The nervous system controls body actions through nerve impulses.

–   certain parts release hormones into blood

–   rest releases neurotransmitters excite or inhibit nerve, muscle & gland cells

–   results in milliseconds, brief duration of effects

 

NERVOUS and ENDOCRINE SYSTEM

•      The nervous system causes muscles to contract or glands to secrete. The endocrine system affects virtually all body tissues by altering metabolism, regulating growth and development, and influencing reproductive processes.

 

•      Parts of the nervous system stimulate or inhibit the release of hormones.

•      Hormones may promote or inhibit the generation of nerve impulses.

 

•      Table 18.1 compares the characteristics of the nervous and endocrine systems.

General Functions of Hormones

•       Help regulate:

–    extracellular fluid

–    metabolism

–    biological clock

–    contraction of cardiac & smooth muscle

–    glandular secretion

–    some immune functions

•       Growth & development

•       Reproduction

 

•       Hormones have powerful effects when present in very low concentrations.

 

Endocrine Glands Defined

•      Exocrine glands

–   secrete products into ducts which empty into body cavities or body surface

–   sweat, oil, mucous, & digestive glands

•      Endocrine glands

–   secrete products (hormones) into bloodstream

–   pituitary, thyroid, parathyroid, adrenal, pineal

–   other organs secrete hormones as a 2nd function

–   hypothalamus, thymus, pancreas,ovaries,testes, kidneys, stomach, liver, small intestine, skin, heart & placenta

Hormone Receptors

•       Hormones only affect target cells with specific membrane proteins called receptors

Hormone Receptors

•      Although hormones travel in blood throughout the body, they affect only specific target cells.

–   Target cells have specific protein or glycoprotein receptors to which hormones bind.

•      Receptors are constantly being synthesized and broken down.

•      Synthetic hormones that block the receptors for particular naturally occurring hormones are available as drugs. (Clinical Application)

Regulation of Hormone Receptors

•      Receptors are constantly being synthesized & broken down

–   range of 2000-100,000 receptors / target cell

 

•      Down-regulation

–   excess hormone leads to a decrease in number of receptors

•   receptors undergo endocytosis and are degraded

–   decreases sensitivity of target cell to hormone

•      Up-regulation

–   deficiency of hormone leads to an increase in the number of receptors

–   target tissue becomes more sensitive to the hormone

Blocking Hormone Receptors

•      Synthetic drugs may block receptors for naturally occurring hormones

–   Normally, progesterone levels drop once/month leading to menstruation.  Progesterone levels are maintained when a woman becomes pregnant.

–   RU486 (mifepristone) binds to the receptors for progesterone preventing progesterone from sustaining the endometrium in a pregnant woman

•   brings on menstrual cycle        

•   used to induce abortion

Circulating and Local Hormones

•      Hormones that travel in blood and act on distant target cells are called circulating hormones or endocrines.

•      Hormones that act locally without first entering the blood stream are called local hormones.

–   Those that act on neighboring cells are called paracrines.

–   Those that act on the same cell that secreted them are termed autocrines.

•      Figure 18.2 compares the site of action of circulating and local hormones.

Circulating & Local Hormones

•      Circulating hormones

•      Local hormones

–   paracrines

–   autocrines

Chemical Classes of Hormones - Overview

•      Table 18.2 provides a summary of the hormones.

•      Lipid-soluble hormones include the steroids, thyroid hormones, and nitric oxide, which acts as a local hormone in several tissues.

•      Water-soluble hormones include the amines; peptides, proteins, and glycoproteins; and eicosanoids.

Lipid-soluble Hormones

•      Steroids

–   lipids derived from cholesterol on SER

–   different functional groups attached to core of structure provide uniqueness

•      Thyroid hormones

–   tyrosine ring plus attached iodines are lipid-soluble

•      Nitric oxide is gas

 

Water-soluble Hormones

•      Amine, peptide and protein hormones

–   modified amino acids or amino acids put together

–   serotonin, melatonin, histamine, epinephrine

–   some glycoproteins

•      Eicosanoids

–   derived from arachidonic acid (fatty acid)

–   prostaglandins or leukotrienes

Hormone Transport in Blood

•      Protein hormones circulate in free form in blood

•      Steroid (lipid) & thyroid hormones must attach to transport proteins synthesized by liver

–   improve transport by making them water-soluble

–   slow loss of hormone by filtration within kidney

–   create reserve of hormone

•   only 0.1% to 10% of hormone is not bound  to transport protein = free fraction

General Mechanisms of Hormone Action

•      Hormone binds to cell surface or receptor inside target cell

•      Cell may then

–    synthesize new molecules

–    change permeability of membrane

–    alter rates of reactions

•      Each target cell responds to hormone differently

At liver cells---insulin stimulates glycogen synthesis

At adipocytes---insulin stimulates triglyceride synthesis

Action of Lipid-Soluble Hormone

•      Lipid-soluble hormones bind to and activate receptors within cells.

–   The activated receptors then alter gene expression which results in the formation of new proteins.

–   The new proteins alter the cells activity and result in the physiological responses of those hormones.

•      Figure 18.3 shows this mechanism of action.

Action of Lipid-Soluble Hormones

•       Hormone diffuses through phospholipid bilayer & into cell

•       Binds to receptor turning on/off specific genes

•       New mRNA is formed & directs synthesis of new proteins

•       New protein alters cell’s activity

Action of Water-Soluble Hormones

•      Water-soluble hormones alter cell functions by activating plasma membrane receptors, which set off a cascade of events inside the cell.

–   The water-soluble hormone that binds to the cell membrane receptor is the first messenger.

–   A second messenger is released inside the cell where hormone stimulated response takes place.

•      A typical mechanism of action of a water-soluble hormone using cyclic AMP as the second messenger is seen in Figure 18.4.

Action of Water-Soluble Hormones

•      The hormone binds to the membrane receptor.

•      The activated receptor activates a membrane G-protein which turns on adenylate cyclase.

•      Adenylate cyclase converts ATP into cyclic AMP which activates protein kinases.

•      Protein kinases phosphorylate enzymes which catalyze reactions that produce the physiological response.

•      Since hormones that bond to plasma membrane receptors initiate a cascade of events, they can induce their effects at very low concentrations.

Action of Water-Soluble Hormones

•       Can not diffuse through plasma membrane

•       Hormone receptors are integral membrane proteins

–    act as first messenger

•       The hormone binds to the membrane receptor.

•       The activated receptor activates a membrane G-protein which turns on adenylate cyclase.

•       Adenylate cyclase converts ATP into cyclic AMP which activates protein kinases.

•       Protein kinases phosphorylate enzymes which catalyze reactions that produce the physiological response.

 

 

Water-soluble Hormones

•      Cyclic AMP is the 2nd messenger

–   kinases in the cytosol speed up/slow down physiological responses

•      Phosphodiesterase inactivates cAMP quickly

•      Cell response is turned off unless new hormone molecules arrive

 Second Messengers

•      Some hormones exert their influence by increasing the synthesis of cAMP

–   ADH, TSH, ACTH, glucagon and epinephrine

•      Some exert their influence by decreasing the level of cAMP

–   growth hormone inhibiting hormone

•      Other substances can act as 2nd messengers

–   calcium ions

–   cGMP

•      A hormone may use different 2nd messengers in different target cells

 

 

Amplification of Hormone Effects

•      Single molecule of hormone binds to receptor

•      Activates 100 G-proteins

•      Each activates an adenylate cyclase molecule which then produces 1000 cAMP

•      Each cAMP activates a protein kinase, which may act upon 1000’s of substrate molecules

•      One molecule of epinephrine may result in breakdown of millions of glycogen molecules into glucose molecules

Cholera Toxin and G Proteins

•      Toxin is deadly because it produces massive watery diarrhea and person dies from dehydration

•      Toxin of cholera bacteria causes G-protein to lock in activated state in intestinal epithelium

•      Cyclic AMP causes intestinal cells to actively transport chloride (Na+ and water follow) into the lumen

•      Person die unless ions and fluids are replaced & receive antibiotic treatment

 

 

Hormonal Interactions

•      The responsiveness of a target cell to a hormone depends on the hormone’s concentration, the abundance of the target cell’s hormone receptors, and influences exerted by other hormones.

•      Three hormonal interactions are the

–   permissive effect

–   synergistic effect

–   antagonist effect

Hormonal Interactions

•      Permissive effect

–   a second hormone, strengthens the effects of the first

–   thyroid strengthens epinephrine’s effect upon lipolysis

•      Synergistic effect

–   two hormones acting together for greater effect

–   estrogen & LH are both needed for oocyte production

•      Antagonistic effects

–   two hormones with opposite effects

–   insulin promotes glycogen formation & glucagon stimulates glycogen breakdown

 

Control of Hormone Secretion

•      Regulated by signals from nervous system, chemical changes in the blood or by other hormones

•      Negative feedback control (most common)

–   decrease/increase in blood level is reversed

•      Positive feedback control

–   the change produced by the hormone causes more hormone to be released

•      Disorders involve either hyposecretion or hypersecretion of a hormone

HYPOTHALAMUS AND PITUITARY GLAND

•      The hypothalamus is the major integrating link between the nervous and endocrine systems.

–   Hypothalamus receives input from cortex, thalamus, limbic system & internal organs

–   Hypothalamus controls pituitary gland with 9 different releasing & inhibiting hormones

 

•      The hypothalamus and the pituitary gland (hypophysis) regulate virtually all aspects of growth, development, metabolism, and homeostasis.

Anatomy of Pituitary Gland

•       The pituitary gland is located in the sella turcica of the sphenoid bone and is differentiated into the anterior pituitary (adenohypophysis), the posterior pituitary (neurohypophysis), and pars intermedia (avascular zone in between (Figures 18.5 and 18.21b).

 

•       Pea-shaped, 1/2 inch gland found in sella turcica of sphenoid

–    Infundibulum attaches it to brain

•       Anterior lobe = 75%

–    develops from roof of mouth

•       Posterior lobe = 25%

–    ends of axons of 10,000 neurons found in hypothalamus

–    neuroglial cells called pituicytes

Anterior Pituitary Gland (Adenohypophysis)

•      The blood supply to the anterior pituitary is from the superior hypophyseal arteries.

•      Hormones of the anterior pituitary and the cells that produce the:

–    Human growth hormone (hGH) is secreted by somatotrophs.

–    Thyroid-stimulating hormone (TSH) is secreted by thyrotrophs.

–    Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are secreted by gonadotrophs.

–    Prolactin (PRL) is secreted by lactrotrophs.

–    Adrenocorticotrophic hormone (ACTH) and melanocyte-stimulating hormone (MSH) are secreted by corticotrophs.

Flow of Blood to Anterior Pituitary

•      Controlling hormones enter blood

•      Travel through portal veins

•      Enter anterior pituitary at capillaries

Anterior Pituitary

Feedback

•      Secretion of anterior pituitary gland hormones is regulated by hypothalamic regulating hormones and by negative feedback mechanisms (Figure 18.6, Table 18.3).

Negative Feedback Systems

•      Decrease in blood levels

•      Receptors in hypothalamus & thyroid

•      Cells activated to secrete more TSH or more T3 & T4

•      Blood levels increase

Positive Feedback

•       Oxytocin stimulates uterine contractions

•       Uterine contractions stimulate oxytocin release

Human Growth Hormone and Insulin-like Growth Factors

•      Human growth hormone (hGH) is the most plentiful anterior pituitary hormone.

•      It acts indirectly on tissues by promoting the synthesis and secretion of small protein hormones called insulin-like growth factors (IGFs).

–   IGFs stimulate general body growth and regulate various aspects of metabolism.

–   Various stimuli promote and inhibit hGH production (Figure 18.7).

–   One symptom of excess hGH is hyperglycemia. (Clinical Application)

Human Growth Hormone

•      Produced by somatotrophs

•      target cells synthesize insulinlike growth

–   common target cells are liver, skeletal muscle, cartilage and bone

–   increases cell growth & cell division by increasing their uptake of amino acids & synthesis of proteins

–   stimulate lipolysis in adipose so fatty acids used for ATP

–   retard use of glucose for ATP production so blood glucose levels remain high enough to supply brain

 

Regulation of hGH

•      Low blood sugar stimulates release of GHRH from hypothalamus

–   anterior pituitary releases more hGH, more glycogen broken down into glucose by liver cells

•      High blood sugar stimulates release of GHIH from hypothalamus

–   less hGH from anterior pituitary, glycogen does not breakdown into glucose

Diabetogenic Effect of Human Growth Hormone

•      Excess of growth hormone

–   raises blood glucose concentration

–   pancreas releases insulin continually

–   beta-cell burnout

•      Diabetogenic effect

–   causes diabetes mellitis if no insulin activity can occur eventually

Thyroid Stimulating Hormone (TSH)

•      Hypothalamus regulates thyrotroph cells

•      Thyrotroph cells produce TSH

•      TSH stimulates the synthesis & secretion of T3 and T4

•      Metabolic rate stimulated

Follicle Stimulating Hormone (FSH)

•      Releasing hormone from       hypothalamus controls                               gonadotrophs

•      Gonadotrophs release                                           follicle stimulating hormone

•      FSH functions

–   initiates the formation of follicles within the ovary

–   stimulates follicle cells to secrete estrogen

–   stimulates sperm production in testes

Luteinizing Hormone (LH)

•      Releasing hormones from hypothalamus stimulate gonadotrophs

•      Gonadotrophs produce LH

•      In females, LH stimulates

–   secretion of estrogen

–   ovulation of 2nd oocyte from ovary

–   formation of corpus luteum

–   secretion of progesterone

•      In males, LH stimulates the interstitial cells of the testes to secrete testosterone.

Prolactin (PRL)

•      Prolactin (PRL), together with other hormones, initiates and maintains milk secretion by the mammary glands.

–   Hypothalamus regulates              lactotroph cells

–   Lactotrophs produce prolactin

–   Under right conditions, prolactin       causes milk production

•      Suckling reduces levels of hypothalamic inhibition and prolactin levels rise along with milk production

Adrenocorticotrophic Hormone

•      Adrenocorticotrophic hormone (ACTH) controls the production and secretion of hormones called glucocorticoids by the cortex of the adrenal gland.

–   Hypothalamus releasing hormones stimulate corticotrophs

–   Corticotrophs secrete ACTH & MSH

–   ACTH stimulates cells of the adrenal cortex that produce glucocorticoids

 

Melanocyte-Stimulating Hormone

•      Melanocyte-stimulating hormone (MSH) increases skin pigmentation although its exact role in humans is unknown.

–   Releasing hormone from hypothalamus increases MSH release from the anterior pituitary

–   Secreted by corticotroph cells

•      Function not certain in humans (increase skin pigmentation in frogs )

Posterior Pituitary Gland (Neurohypophysis)

•      Although the posterior pituitary gland does not synthesize hormones, it does store and release two hormones.

–   Hormones made by the hypothalamus and stored in the posterior pituitary are oxytocin (OT) and antidiuretic hormone (ADH).

–   The neural connection between the hypothalamus and the neurohypophysis is via the hypothalamohypophyseal tract (Figure 18.8).

Posterior Pituitary Gland (Neurohypophysis)

•      Does not synthesize hormones

•      Consists of axon terminals of hypothalamic neurons

•      Neurons release two neurotransmitters into capillaries

–   antidiuretic hormone

–   oxytocin

Oxytocin

•       Two target tissues both involved in neuroendocrine reflexes

•       During delivery

–    baby’s head stretches cervix

–    hormone release enhances uterine muscle contraction

–    baby & placenta are delivered

•       After delivery

–    Oxytocin stimulates contraction of the uterus and ejection (let-down) of milk from the breasts.

•    Nursing a baby after delivery stimulates oxytocin release, promoting uterine contractions and the expulsion of the placenta (Clinical Application).

•    suckling & hearing baby’s cry stimulates milk ejection

 

Oxytocin during Labor

•      Stimulation of uterus by baby

•      Hormone release from posterior pituitary

•      Uterine smooth muscle contracts until birth of baby

•      Baby pushed into cervix, increase hormone release

•      More muscle contraction occurs

•      When baby is born, positive feedback ceases

ADH

•      Antidiuretic hormone stimulates water reabsorption by the kidneys and arteriolar constriction.

•      The effect of ADH is to decrease urine volume and conserve body water.

•      ADH is controlled primarily by osmotic pressure of the blood (Figure 18.9).

Antidiuretic Hormone (ADH)

•      Known as vasopressin

•      Functions

–   decrease urine production

–   decrease sweating

–   increase BP

Regulation of ADH

•      Dehydration

–   ADH released

•      Overhydration

–   ADH inhibited

THYROID GLAND - Overview

•      The thyroid gland is located just below the larynx and has right and left lateral lobes (Figure 18.10a).

•      Histologically, the thyroid consists of the thyroid follicles composed of follicular cells, which secrete the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃), and parafollicular cells, which secrete calcitonin (CT) (Figures 18.10b and 18.13c).

Thyroid Gland

•      On each side of trachea is lobe of thyroid

•      Weighs 1 oz & has rich blood supply

Histology of Thyroid Gland

•      Follicle = sac of  stored hormone (colloid) surrounded by follicle cells that produced it

–   T3 & T4

•      Inactive cells are short

•      In between cells called parafollicular cells

–    produce calcitonin

 

Photomicrograph of Thyroid Gland

Formation, Storage, and Release of Thyroid Hormones

•      Thyroid hormones are synthesized from iodine and tyrosine within a large glycoprotein molecule called thyroglobulin (TGB) and are transported in the blood by plasma proteins, mostly thyroxine-binding globulin (TBG).

•      The formation, storage, and release steps include

–   iodide trapping,

–   synthesis of thyroglobulin,

–   oxidation of iodide,

–   iodination of tyrosine,

–   coupling of T₁ and T₂,

–   pinocytosis and digestion of colloid,

–   secretion of thyroid hormones, and transport in blood (Figure 18.11).

Formation of Thyroid Hormone

•      Iodide trapping by follicular cells

•      Synthesis of thyroglobulin (TGB)

•      Release of TGB into colloid

•      Iodination of tyrosine in colloid

•      Formation of T3 & T4 by combining T1 and T2 together

•      Uptake & digestion of TGB by follicle cells

•      Secretion of T3 & T4 into blood

 

 

Actions of Hormones from Thyroid  Gland

•      T3 & T4

–   thyroid hormones responsible for our metabolic rate, synthesis of protein, breakdown of fats, use of glucose for ATP production

•      Calcitonin

–   responsible for building of bone & stops reabsorption of bone (lowers blood levels of Calcium)

Control of T3 & T4  Secretion

•      Negative feedback system

•      Low blood levels of hormones stimulate hypothalamus

•      It stimulates pituitary to release TSH

•      TSH stimulates gland to raise blood levels

PARATHYROID GLANDS

•      The parathyroid glands are embedded on the posterior surfaces of the lateral lobes of the thyroid

–   principal cells produce parathyroid hormone

–   oxyphil cells … function is unknown (Figure 18.13).

•      Parathyroid hormone (PTH) regulates the homeostasis of calcium and phosphate

•   increase blood calcium level

•   decrease blood phosphate level

–   increases the number and activity of osteoclasts

–   increases the rate of Ca⁺² and Mg⁺² from reabsorption from urine and inhibits the reabsorption of HPO₄^-2 so more is secreted in the urine

–   promotes formation of calcitriol, which increases the absorption of Ca⁺², Mg⁺²,and HPO₄^-2 from the GI tract

Parathyroid Glands

•      4 pea-sized glands found on back of thyroid gland

Histology of Parathyroid Gland

•      Principal cells produce parathyroid hormone (PTH)

•      Oxyphil cell function is unknown

Blood Calcium

•      Blood calcium level directly controls the secretion of calcitonin and parathyroid hormone via negative feedback loops that do not involve the pituitary gland (Figure 18.14).

•      Table 18.7 summarizes the principal actions and control of secretion of parathyroid hormone.

Regulation of Calcium Blood Levels

•       High or low blood levels of Ca+2 stimulate the release of different hormones --- PTH or CT

Adrenal Glands

•       The adrenal glands are located superior to the kidneys (Figure 18.15)

•       3 x 3 x 1 cm in size and weighs 5 grams

•       consists of an outer cortex and an inner medulla.

–    Cortex produces  3 different types of hormones from 3 zones of cortex

–    Medulla produces epinephrine & norepinephrine

Adrenal Cortex

•      The adrenal cortex is divided into three zones, each of which secretes different hormones (Figure 18.15).

–   The zona glomerulosa (outer zone)

•   secretes mineralocorticoids.

–   The zona fasciculata (middle zone)

•   secretes glucocorticoids.

–   The zona reticularis (inner zone)

•   secretes androgens.

Histology of Adrenal
Gland

•      Cortex

–   3 zones

•      Medulla

Structure of Adrenal Gland

•       Cortex derived from mesoderm

•       Medulla derived from ectoderm

Mineralocorticoids

•      95% of hormonal activity due to aldosterone

•      Functions

–   increase reabsorption of Na+ with Cl- , bicarbonate and water following it

–   promotes excretion of K+ and H+

•      Hypersecretion = tumor producing aldosteronism

–   high blood pressure caused by retention of Na+ and water in blood

Regulation of Aldosterone

Glucocorticoids

•      95% of hormonal activity is due to cortisol

•      Functions = help regulate metabolism

–   increase rate of protein catabolism & lipolysis

–   conversion of amino acids to glucose

–   stimulate lipolysis

–   provide resistance to stress by making nutrients available for ATP production

–   raise BP by vasoconstriction

–   anti-inflammatory effects reduced (skin cream)

•   reduce release of histamine from mast cells

•   decrease capillary permeability

•   depress phagocytosis

 

Regulation of Glucocorticoids

•      Negative feedback

Androgens from Zona Reticularis

•      Small amount of male hormone produced

–   insignificant in males

–   may contribute to sex drive in females

–   is converted to estrogen in postmenopausal females

Adrenal Medulla

•      Chromaffin cells receive direct innervation from sympathetic nervous system

–   develop from same tissue as postganglionic neurons

•      Produce epinephrine & norepinephrine

•      Hormones are sympathomimetic

–   effects mimic those of sympathetic NS

–   cause fight-flight behavior

•      Acetylcholine increase hormone secretion by adrenal medulla

PANCREATIC ISLETS

•      The pancreas is a flattened organ located posterior and slightly inferior to the stomach and can be classified as both an endocrine and an exocrine gland (Figure 18.18).

•      Histologically, it consists of pancreatic islets or islets of Langerhans (Figure 18.19) and clusters of cells (acini) (enzyme-producing exocrine cells).

Anatomy of Pancreas

•       Organ (5 inches) consists of head, body & tail

•       Cells (99%) in acini pro