ENDOCRINE SYSTEM

PHYSIOLOGY

Endocrine vs Nervous System

NERVOUS ENDOCRINE

• Uses action potentials along axons and chemical neurotransmitters at synapses

• Uses chemical hormones released from glands into the blood

• Receptors are on post-synaptic membrane

• Receptors are on the plasma membranes of target cells or intercellular

• Signals are very fast (milliseconds)

• Signals are slower (seconds to days)

• Response is immediate but short-lived

• Response is delayed but more sustained

Endocrine glands are ductless glands

Fig. 11.1P. 286

Blurring the edges

Specialized neurons can secrete chemicals into the blood rather than synaptic cleft.• Chemical secreted is called neurohormone.• Hypothalamus primary secretor of

neurohormones.

Some chemicals like norepinephrine is both a neurotransmitter and a hormone.

Characteristics of Hormones

• Hormones:– exert their effects some distance from where

they are produced– are active under very low (picogram to

nanogram) concentrations in the blood– usually have a short half-life in the body -

several seconds to 60 mins. They are degraded by enzymes in their target cells or in the kidney or liver.

Characteristics of Hormones

• Hormones bring about their effects by altering cell activity. The precise response depends on the target cell type. Typical cellular effects include:– Altering plasma membrane permeability– Stimulating protein synthesis– Activating enzymes– Inducing secretory activity– Stimulating mitosis

Characteristics of Hormones

• Hormones levels depend on:– Rate of release– Speed of inactivation and removal from

the body

• Pharmacological levels of a hormone may have different functions than physiological levels of the hormone

Chemical Classes of Hormones

• Amines - Derived from tyrosine or tryptophan. Includes: epinephrine, T4, and melatonin.

• Proteins and peptides - Made from amino acid chains. Includes: antidiuretic hormone, growth hormone, and insulin.

• Glycoproteins - A polypeptide chain bound to one or more carbohydrates. Includes: follicle-stimulating hormone and luteinizing hormone.

• Steroids - Lipids derived from cholesterol. Includes: testosterone, estradiol, and cortisol.

Chemical Classes of Hormones• Hormones can also be divided into:

– Polar:• H20 soluble.

– Catecholamines, peptides, and glycoproteins

– Nonpolar (lipophilic):• H20 insoluble (but lipid soluble).

– Can gain entry into target cells– Steroid hormones and T4

– Pineal gland secretes melatonin:• Has properties of both H20 soluble and lipophilic hormones.

Control of Hormone Release

• Synthesis and release of most hormones are regulated by a negative feedback system. As hormone levels rise, they cause target organ effects which inhibit further hormone release.

Hormone - Target Cell Specificity

• Hormones circulate to virtually all tissues but influence the activity of only certain tissue cells, known as its target cells.

Hormone - Target Cell Specificity

• Hormone-receptor interaction depends upon three factors:– Blood levels of the hormone

– Relative number of receptors for that hormone on the target cell

– Affinity of the bond between the hormone and the receptor

Hormone - Target Cell Specificity

• Receptors are dynamic structures: they can respond to rising levels of hormones by increasing in number (up-regulation) or respond to prolonged exposure to high hormone concentrations by reducing the number of receptors (down-regulation).

Mechanisms of Hormone Action

• Hormones:– Diffuse through the cell membrane and

bind to intracellular receptors (steroid hormones & T4) or bind to receptors on the membrane of distant cells (amino-acid based hormones).

– Carry out their effects by direct gene activation (steroids) or through signal transduction systems (amino-acid based).

Lipophilic steroid and thyroid hormones are attached to plasma carrier proteins.

Hormones dissociate from carrier proteins to pass through lipid component of the target plasma membrane.

Receptors for the lipophilic hormones are known as nuclear hormone receptors.Steroid receptors function within cell to activate gene transcription.

Fig. 11.4P. 292

Each nuclear hormone receptor has 2 regions:

A ligand (hormone)-binding domain.DNA-binding domain.

Receptor must be activated by binding to hormone before binding to specific region of DNA called HRE (hormone responsive element).

Located adjacent to gene that will be transcribed.

Fig. 11.5P. 293

Fig. 11.3P. 289

The carrier protein for T4 is thyroxine-binding globulin (TBG).Free T4 passes into cytoplasm and is converted to T3.Nonspecific binding proteins shuttle it to the nucleusReceptor proteins are in the nucleus.

Fig. 11.6P. 294

T3 binds to ligand-binding domain. Other half-site is vitamin A derivative (9-cis-retinoic acid).

DNA-binding domain can then bind to the half-site of the HRE.

Two partners can bind to the DNA to activate HRE.

Stimulate transcription of genes.

Fig. 11.7P. 294

Adenylate Cyclase-cAMP

Fig. 11.8P. 295

Polypeptide or glycoprotein hormones bind to receptor protein causing dissociation of a subunit of G-protein.

G-protein subunit binds to and activates adenylate

cyclase. ATP cAMP + PPi

cAMP attaches to inhibitory subunit of protein kinase.Inhibitory subunit dissociates and protein kinase is activated.

Phosphorylates enzymes within the cell to produce hormone’s effects.

cAMP inactivated by phosphodiesterase, which hydrolyzes cAMP to inactive fragments.

Phospholipase-C-Ca2+

Fig. 11.9P. 297

Ca2+ diffuses into the cytoplasm and binds to calmodulin.Calmodulin activates specific protein kinase enzymes.

Phospholipase-C-Ca2+

Epi Can Act Through Two 2nd Messenger Systems

Fig. 11.10P. 297

Tyrosine KinaseStimulate glycogen, fat and protein synthesis.Stimulate insertion of GLUT-4 carrier proteins.

Fig. 11.11P. 298

GLANDHORMONETARGET ORGAN

NORMAL EFFECTS OF HORMONE

EFFECTS OF HYPER- AND HYPOSECRETION

CONTROL OF RELEASE

Pituitary gland (hypophysis) is located in the diencephalon.Structurally and functionally divided into:

Anterior lobe = AdenohypophysisPosterior lobe = Neurohypophysis

Pituitary

Fig. 11.12P. 299

Pituitary• Anterior pituitary (adenohypophysis):

– Master gland– Derived from a pouch of epithelial tissue that migrates

upward from the mouth.• Consists of 2 main parts:

– Pars distalis: anterior portion.– Pars tuberalis: thin extension in contact with the infundibulum.

• Posterior pituitary(neurohypophysis):– Formed by downgrowth of the brain during fetal

development.– Is in contact with the infundibulum.

Pituitary Hormones

Fig. 11.14P. 302

Gonadotropins

• The gonadotropins are:– Follicle-stimulating hormone (FSH) -

Responsible for gamete production in both sexes. – Luteinizing Hormone (LH) - In females works

with FSH to cause follicle development, and then independently is responsible for ovulation. In males it is sometimes called interstitial cell-stimulating hormone (ICSH), because it stimulates the interstitial cells to produce testosterone

THYROID-STIMULATING HORMONE

• Thyroid-stimulating Hormone (Thyrotropin; TSH) - chain of 96 amino acids; chain of 112 amino acids.– Acts on the thyroid follicle cells to

stimulate thyroid hormone synthesis

ADRENOCORTICOTROPIC HORMONE

• Adrenocorticotropic Hormone (ACTH) - polypeptide of 39 amino acids– Stimulates cells of adrenal cortex to

increase steroid synthesis and secretion

GROWTH HORMONE

• Growth Hormone (Somatotropin) - protein of 191 amino acids.– General anabolic stimulant– Works by stimulating production of an

insulin-like growth factor (IGF-1; somatomedin C) in the liver

– IGF-1 stimulates uptake of amino acids and sulfur, particularly on developing bone, and mobilizes fat from fat depots

GROWTH HORMONE

• Gigantism refers to a condition characterized by extreme physical size and stature due to a hypersecretion of growth hormone during infancy, childhood or adolescence

12 year-old with mother

GROWTH HORMONE

• Dwarfism results from a GH deficiency in childhood, leading to a maximum height of 4 feet typically with normal body proportions. If diagnosed before puberty, hormone replacement therapy can promote nearly normal growth.Dwarfed brothers with

researcher in India

PROLACTIN

• Prolactin (PRL) - Protein hormone of 199 amino acids. In females it stimulates milk production by the mammary glands. There is some evidence it enhances testosterone production in males.

• Release is inhibited in non-pregnant women. As estrogen and progesterone levels rise late in pregnancy, it stimulates prolactin release.

PROLACTIN• Hyperprolactinaemia

can cause menstrual problems in females and breast enlargement in males.

• Pituitary tumors is a major cause of the condition.

MELANOCYTE-STIMULATING HORMONE

• Melanocyte-stimulating Hormone (MSH) - Derived from a prohormone called pro-opiomelanocortin (POMC) - chain of 13 amino acids; chain of 18 amino acids; chain of 12 amino acids. The major products of POMC is -endorphins, MSH, and ACTH.

MELANOCYTE-STIMULATING HORMONE

– Stimulates pigmentation in fishes, amphibians and reptiles by enhancing the dispersion of melanin from melanocytes

– In birds and mammals, blood levels are insignificant. It will cause darkening of the skin if injected into the circulation, but may be more important as a neurotransmitter in humans than in skin pigmentation.

NEUROHYPOPHYSIS• Hypothalamus neuron

cell bodies produce:– ADH: supraoptic nuclei.– Oxytocin:

paraventricular nuclei.

• Transported along the hypothalamo-hypophyseal tract.

• Stored and released from posterior pituitary.

Fig. 11.13P. 301

ANTIDIURETIC HORMONE

• Antidiuretic Hormone (ADH; vasopressin) - oligopeptide of 9 amino acids.– The main regulator of body fluid osmolarity– Increases the reabsorption rate of water in

kidney tubule cells; under high concentrations promotes vasoconstriction

– Secretion is regulated in the hypothalamus by osmoreceptors, which sense water concentration

OXYTOCIN

• Oxytocin - oligopeptide of 9 amino acids

• hormonal trigger for milk ejection (the letdown reflex) in women whose breasts are actively producing milk

• a strong stimulant of uterine contraction, and is released in progressively greater amounts as birth nears.

Hypothalamic Control of the Anterior Pituitary

Hormonal control rather than neural.Hypothalamus neurons synthesize releasing and inhibiting hormones.Hormones secreted into the hypothalamo-hypophyseal portal system regulate the secretions of the anterior pituitary

Fig. 11.15P. 303

Secretions are controlled by negative feedback inhibition by target gland hormones.

Negative feedback at 2 levels:

The target gland hormone can act on the hypothalamus and inhibit secretion of releasing hormones.The target gland hormone can act on the anterior pituitary and inhibit response to the releasing hormone.

Fig. 11.17P. 304

Adrenal Gland

• Paired organs that cap the kidneys.

• Each gland consists of an outer cortex and inner medulla.

Adrenal cortex:Does not receive neural innervation.Must be stimulated hormonally (ACTH).

Consists of 3 zones:

Zona glomerulosa. Zona fasciculata. Zona reticularis.

Secretes corticosteroids.

Adrenal Cortex

Fig. 11.18P. 305

Corticosteroids• Zona glomerulosa:

– Mineralcorticoids (aldosterone):• Stimulate kidneys to reabsorb Na+ and secrete K+ by

stimulating transcription of Na+/K+ pumps..

• Zona fasciculata:– Glucocorticoids (cortisol):

• Inhibit glucose utilization and stimulate gluconeogenesis.

• Zona reticularis (DHEA):– Gonadocorticoids:

• Supplemental sex hormones.

GLUCOCORTICOIDS• At high concentrations, cortisol has

pronounced anti-inflammatory and anti-immune effects including:– Depressing cartilage and bone formation– Inhibiting inflammation by stabilizing

lysosomal membranes

GLUCOCORTICOIDS

• Cushing’s disease results from glucorticoid excess. It is often a result of administration of pharmacological doses of glucocorticoid drugs. Symptoms include persistent hyperglycemia, loss of muscle and bone protein, moon face, and a redistribution of fat to the abdomen and posterior neck (causing a “buffalo hump”).

GLUCOCORTICOIDS

• Addison’s disease is the major hyposecretory disorder of the adrenal cortex, usually involving of both glucocorticoids and mineralcorticoids. Victims lose weight, demonstrate hypoglycemia and reduced levels of sodium, and show an increase in skin pigmentation (bronzing) due to increased ACTH levels.

JFK had Addison’s, which he kept from public knowledge

GONADOCORTICOIDS• Androgenital syndrome -

hypersecretion of androgens from the adrenal cortex. Most often apparent in women (since the gonadal levels of androgens often mask the effects in men), it manifests itself in hirsutism and growth of the clitoris to resemble a small penis.

Olga Roderick, the “Bearded Lady”

Fig. 11.19P. 306

Adrenal medulla:Derived from embryonic neural crest ectoderm (same tissue that produces the sympathetic ganglia).Synthesizes and secretes:

Catecholamines (mainly Epi but some NE).

Adrenal Medulla

Innervated by preganglionic sympathetic axons.

Increase respiratory and heart rate. Constrict blood vessels, thus increasing venous return.Stimulate glycogenolysis and lipolysis.

Adrenal Medulla

Thyroid gland is located just below the larynx.Thyroid is the largest of the pure endocrine glands.Follicular cells secrete thyroxine.Parafollicular cells secrete calcitonin.

Thyroid Gland

Fig. 11.21aP. 308

Production of Thyroid Hormones

Fig. 11.23P. 309

Iodide (I-) actively transported into the follicle and secreted into the colloid. Oxidized to iodine (Io).

Iodine attached to tyrosine within thyroglobulin chain.Attachment of 1 iodine produces monoiodotyrosine (MIT).Attachment of 2 iodines produces diiodotyrosine (DIT).

MIT and DIT together produce T3

2 DIT molecules coupled together produce T4

TSH stimulates pinocytosis into the follicular cell.Enzymes hydrolyze T3 and T4 from thyroglobulin.

Attached to TBG and released into blood.

T3

• T3 is about ten times more active than T4, and most peripheral tissue have enzymes that can convert T4 to T3 by removing one iodine group. Actions of T3 include:

• Stimulates protein synthesis.• Increases metabolic rate and heat.

– Stimulates increased consumption of glucose and fatty acids.

• Stimulates rate of cellular respiration.• Important regulator in tissue growth and development.

A lack of negative feedback inhibition stimulates TSH, which causes abnormal growth.

Fig. 11.25P. 310

Goiter - Due to iodinedeficiency

Hypothyroid in Adults

– Adult myxedema:• Accumulation of

mucoproteins and fluid in subcutaneous tissue.

– Symptoms:• Decreased metabolic rate.• Weight gain.• Decreased ability to adapt

to cold.• Lethargy.

Hypothyroid in Infants

– Cretinism:– Hypothyroid from end

of 1st trimester to 6 months postnatally.

• Severe mental retardation

• Short disproportionately sized body with a thick neck and tongue

Hyperthyroid in Adults

• Grave’s disease:– Autoimmune disorder:

• Exerts TSH-like effects on thyroid.

• Elevated metabolic rate (rapid heartbeat, sweating, nervousness) and exophthalmos (protrusion of the eyeballs).

HORMONES OF CALCIUM BALANCE

• Calcitonin - protein of 32 amino acids.– Produced by thyroid

parafollicular cells– Reduces serum calcium levels

by inhibiting osteoclast activity and stimulating calcium uptake in bone

– Important only in childhood when bones are quickly growing

HORMONES OF CALCIUM BALANCE

• Parathyroid Hormone - protein of 84 amino acids.– Produced by parathyroid

glands– Increases serum calcium

levels by stimulating osteoclasts, enhancing absorption of calcium in the small intestine, and promoting Ca2+ reabsorption in the kidney

Fig. 11.28P. 312

Fig. 11.29P. 312

Pancreatic Islets (of Langerhans)

Fig. 11.30P. 313

GLUCAGON

• Alpha cells secrete glucagon - peptide of 29 amino acids.– Stimulus for release is decrease in blood

glucose levels– Synthesized as a larger proglucagon molecule

and then clipped down by enzymes– Potent hyperglycemic agent - major target

organ is the liver– Stimulates glycogenolysis and lipolysis

INSULIN

• Beta cells secrete insulin - peptide of 51 amino acids.– Synthesized as a larger proinsulin molecule and

then clipped down by enzymes.– Lowers blood glucose by enhancing membrane

transport of glucose into body cells (especially muscle and fat cells). The brain, kidney and liver have easy access to glucose and do not require insulin.

– Inhibits glycogenolysis and gluconeogenesis

INSULIN• After glucose enters a target cell,

insulin binding triggers enzymatic activity that:– Catalyze the oxidation of glucose for

ATP production– Join glucose molecules together to form

glycogen – Convert excess glucose to fat

Fig. 11.31P. 313

INSULIN

• Diabetes mellitus results from hyposecretion of insulin or hypoactivity of insulin. When insulin is absent or deficient, blood sugar levels remain high after a meal because glucose is unable to enter most tissue cells.

DIABETES• Type I diabetes mellitis (insulin-

dependent) afflicts 750, 000 Americans.– Autoimmune disease (beta cells are

attacked by immune cells). May be due to a virus entering the body and mimicking beta cell antigens.

– Insulin is not produced or secreted, requiring regular insulin

injections.

DIABETES

• Type II diabetes mellitis (non-insulin-dependent) afflicts 7.5 million Americans.– Insulin resistance - Insulin is usually

produced but the receptors do not respond.– The membrane protein PC-1 may be a

culprit - it has been shown to inhibit the tyrosine kinase receptor, but its mechanisms of action are unknown.

DIABETES– Heredity plays a role - an estimated 30% of

Americans carry a gene that predisposes them to Type II diabetes.

– Lifestyle play a role - Type II diabetics are almost always obese and sedentary. Adipose tissue produces a hormone-like chemical called tumor necrosis factor-alpha, which depresses synthesis the cellular glucose transporter (glut-4). Cells cannot take up glucose in the absence of glut-4.

DIABETES

• Three clinical signs of diabetes:– Hyperglycemia -normal blood sugar

should be 80 - 120 mg/dl.– Glucosuria - glucose spills into the urine

at high blood concentrations (300 mg/dl). – Ketoacidosis and ketouria - as sugar is

not available for fuel and lipolysis accelerates.

PINEAL GLAND• Secretes melatonin:

– Production stimulated by the suprachiasmatic nucleus (SCN) in hypothalamus.

• SCN is primary center for circadian rhythms.

• Melatonin secretion increases with darkness and peaks in middle of night.

– May inhibit GnRH.– May function in the

onset of puberty (controversial).

Fig. 11.32P. 314

MELATONIN

• Melatonin secretion has been linked to seasonal affective disorder (SAD) in people living in northern latitudes like Alaska. Melatonin is elevated in the winter months, and it may lead to depression, long bouts of sleeping, and eating binges. Sun lamps with a full spectrum of light are helpful therapy for some people.

The Midnight Sun

Gonads and Placenta

• Gonads (testes and ovaries):– Secrete sex hormones.

• Testosterone.• Estradiol 17-b.• Progesterone.

• Placenta:– Secretes large amounts of estriol, progesterone,

human chorionic gonadotropin (hCG).