Endocrine system maintains homeostasis

The concept that hormones acting on distant target cells to maintain the stability of the internal milieu was a major advance in physiological understanding.

The secretion of the hormone was evoked by a change in the milieu and the resulting action on the target cell restored the milieu to normal.The desired return to the status quo results in the maintenance of homeostasis

Endocrine vs. Nervous System• Major communication systems in the body• Integrate stimuli and responses to changes in

external and internal environment• Both are crucial to coordinated functions of

highly differentiated cells, tissues and organs• Unlike the nervous system, the endocrine

system is anatomically discontinuous.

Hormones travel via the bloodstream to target cells

•The endocrine system broadcasts its hormonal messages to essentially all cells by secretion into blood and extracellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

A cell is a target because is has a specific receptor for the hormone

Most hormones circulate in blood, coming into contact with essentially all cells. However, a given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for the hormone.

Principal functions of the endocrine system

• Maintenance of the internal environment in the body (maintaining the optimum biochemical environment).

• Integration and regulation of growth and development.

• Control, maintenance and instigation of sexual reproduction, including gametogenesis, coitus, fertilization, fetal growth and development and nourishment of the newborn.

Types of cell-to-cell signalingClassic endocrine hormones travel via bloodstream to target cells; neurohormones are released via synapses and travel via the bloostream; paracrine hormones act on adjacent cells and autocrine hormones are released and act on the cell that secreted them. Also, intracrine hormones act within the cell that produces them.

Response vs. distance traveledEndocrine action: the hormone is distributed in blood and binds to distant target cells.Paracrine action: the hormone acts locally by diffusing from its source to target cells in the neighborhood.Autocrine action: the hormone acts on the same cell that produced it.

Major hormones and systems• Top down organization of endocrine system.• Hypothalamus produces releasing factors that

stimulate production of anterior pituitary hormone which act on peripheral endocrine gland to stimulate release of third hormone– Specific examples to follow

• Posterior pituitary hormones are synthesized in neuronal cell bodies in the hypothalamus and are released via synapses in posterior pituitary. – Oxytocin and antidiuretic hormone (ADH)

Types of hormones

• Hormones are categorized into four structural groups, with members of each group having many properties in common: – Peptides and proteins – Amino acid derivatives – Steroids – Fatty acid derivatives - Eicosanoids

Range from 3 amino acids to hundreds of amino acids in size.

Often produced as larger molecular weight precursors that are proteolytically cleaved to the active form of the hormone.

Peptide/protein hormones are water soluble.Comprise the largest number of hormones–

perhaps in thousands

Peptide/protein hormones

Peptide/protein hormones• Are encoded by a specific gene which is transcribed into

mRNA and translated into a protein precursor called a preprohormone

• Preprohormones are often post-translationally modified in the ER to contain carbohydrates (glycosylation)

• Preprohormones contain signal peptides (hydrophobic amino acids) which targets them to the golgi where signal sequence is removed to form prohormone

• Prohormone is processed into active hormone and packaged into secretory vessicles

Peptide/protein hormones• Secretory vesicles move to plasma membrane where they

await a signal. Then they are exocytosed and secreted into blood stream

• In some cases the prohormone is secreted and converted in the extracellular fluid into the active hormone: an example is angiotensin is secreted by liver and converted into active form by enzymes secreted by kidney and lung

Peptide/protein hormone synthesis

Amine hormonesThere are two groups of hormones derived from the

amino acid tyrosineThyroid hormones and Catecholamines

Thyroid Hormone Thyroid hormones are basically a "double" tyrosine with

the critical incorporation of 3 or 4 iodine atoms. Thyroid hormone is produced by the thyroid gland and

is lipid soluble Thyroid hormones are produced by modification of a

tyrosine residue contained in thyroglobulin, post-translationally modified to bind iodine, then proteolytically cleaved and released as T4 and T3. T3 and T4 then bind to thyroxin binding globulin for transport in the blood

Thyroid hormones

Catecholamine hormones Catecholamines are both neurohormones and

neurotransmitters. These include epinephrine, and norepinephrine Epinephrine and norepinephrine are produced by

the adrenal medulla both are water soluble Secreted like peptide hormones

Synthesis of catecholamines

Amine Hormones

• Two other amino acids are used for synthesis of hormones:

• Tryptophan is the precursor to serotonin and the pineal hormone melatonin

• Glutamic acid is converted to histamine

All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it.

All steroid hormones are lipid soluble

Steroid hormones

Types of steroid hormones

• Glucocorticoids; cortisol is the major representative in most mammals

• Mineralocorticoids; aldosterone being most prominent

• Androgens such as testosterone • Estrogens, including estradiol and estrone • Progestogens (also known a progestins) such

as progesterone

Steroid hormones• Are not packaged, but synthesized and immediately

released• Are all derived from the same parent compound:

Cholesterol• Enzymes which produce steroid hormones from

cholesterol are located in mitochondria and smooth ER

• Steroids are lipid soluble and thus are freely permeable to membranes so are not stored in cells

Steroid hormones• Steroid hormones are not water soluble so have to

be carried in the blood complexed to specific binding globulins.

• Corticosteroid binding globulin carries cortisol• Sex steroid binding globulin carries testosterone and

estradiol• In some cases a steroid is secreted by one cell and is

converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain

Steroids can be transformed to active steroid in target cell

Steroidogenic EnzymesCommon name "Old" name Current name

Side-chain cleavage enzyme; desmolase

P450SCC CYP11A1

3 beta-hydroxysteroid dehydrogenase

3 beta-HSD 3 beta-HSD

17 alpha-hydroxylase/17,20 lyase P450C17 CYP17

21-hydroxylase P450C21 CYP21A2

11 beta-hydroxylase P450C11 CYP11B1

Aldosterone synthase P450C11AS CYP11B2

Aromatase P450aro CYP19

Steroid hormone synthesis

All steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates.

The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR)

Steroid hormone synthesis

•The cholesterol precursor comes from cholesterol synthesized within the cell from acetate, from cholesterol ester stores in intracellular lipid droplets or from uptake of cholesterol-containing low density lipoproteins.

•Lipoproteins taken up from plasma are most important when steroidogenic cells are chronically stimulated.

cholesterol

Extracellularlipoprotein

Cholesterolpool

LH

ATP

cAMPPKA+

Pregnenolone

Progesterone

Androstenedione

TESTOSTERONE

3HSD

P450c17

17HSD

acetate

1,25-dihydroxy Vitamin D3 is also derived from cholesterol and is lipid soluble

Not really a “vitamin” as it can be synthesized de novo

Acts as a true hormone

1,25-Dihydroxy Vitamin D3

Fatty Acid Derivatives - Eicosanoids

• Arachadonic acid is the most abundant precursor for these hormones. Stores of arachadonic acid are present in membrane lipids and released through the action of various lipases. The specific eicosanoids synthesized by a cell are dictated by the battery of processing enzymes expressed in that cell.

• These hormones are rapidly inactivated by being metabolized, and are typically active for only a few seconds.

Fatty Acid Derivatives - Eicosanoids

• Eicosanoids are a large group of molecules derived from polyunsaturated fatty acids.

• The principal groups of hormones of this class are prostaglandins, prostacyclins, leukotrienes and thromboxanes.

Regulation of hormone secretion

Sensing and signaling: a biological need is sensed, the endocrine system sends out a signal to a target cell whose action addresses the biological need. Key features of this stimulus response system are: receipt of stimulus synthesis and secretion of hormone delivery of hormone to target cell evoking target cell response degradation of hormone

Control of Endocrine Activity

•The physiologic effects of hormones depend largely on their concentration in blood and extracellular fluid. •Almost inevitably, disease results when hormone concentrations are either too high or too low, and precise control over circulating concentrations of hormones is therefore crucial.

Control of Endocrine Activity

The concentration of hormone as seen by target cells is determined by three factors:

•Rate of production•Rate of delivery•Rate of degradation and elimination

Control of Endocrine Activity

Rate of production: Synthesis and secretion of hormones are the most highly regulated aspect of endocrine control. Such control is mediated by positive and negative feedback circuits, as described below in more detail.

Control of Endocrine Activity

Rate of delivery: An example of this effect is blood flow to a target organ or group of target cells - high blood flow delivers more hormone than low blood flow.

Control of Endocrine Activity

Rate of degradation and elimination: Hormones, like all biomolecules, have characteristic rates of decay, and are metabolized and excreted from the body through several routes. Shutting off secretion of a hormone that has a very short half-life causes circulating hormone concentration to plummet, but if a hormone's biological half-life is long, effective concentrations persist for some time after secretion ceases.

Feedback Control of Hormone Production

Feedback loops are used extensively to regulate secretion of hormones in the hypothalamic-pituitary axis. An important example of a negative feedback loop is seen in control of thyroid hormone secretion

Inputs to endocrine cells

Neural control

• Neural input to hypothalamus stimulates synthesis and secretion of releasing factors which stimulate pituitary hormone production and release

Chronotropic control

• Endogenous neuronal rhythmicity• Diurnal rhythms, circadian rhythms (growth

hormone and cortisol), Sleep-wake cycle; seasonal rhythm

Episodic secretion of hormones

• Response-stimulus coupling enables the endocrine system to remain responsive to physiological demands

• Secretory episodes occur with different periodicity

• Pulses can be as frequent as every 5-10 minutes

• The most prominent episodes of release occur with a frequency of about one hour—referred to as circhoral

• An episode of release longer than an hour, but less than 24 hours, the rhythm is referred to as ultradian

• If the periodicity is approximately 24 hours, the rhythm is referred to as circadian – usually referred to as diurnal because the increase in

secretory activity happens at a defined period of the day.

Episodic secretion of hormones

Circadian (chronotropic) control

Circadian Clock

Physiological importance of pulsatile hormone release

• Demonstrated by GnRH infusion • If given once hourly, gonadotropin secretion and

gonadal function are maintained normally • A slower frequency won’t maintain gonad function • Faster, or continuous infusion inhibits gonadotropin

secretion and blocks gonadal steroid production

Clinical correlate

• Long-acting GnRH analogs (such as leuproline) have been applied to the treatment of precocious puberty, to manipulate reproductive cycles (used in IVF), for the treatment of endometriosis, PCOS, uterine leiomyoma etc

Feedback control

• Negative feedback is most common: for example, LH from pituitary stimulates the testis to produce testosterone which in turn feeds back and inhibits LH secretion

• Positive feedback is less common: examples include LH stimulation of estrogen which stimulates LH surge at ovulation

Negative feedback effects of cortisol

Substrate-hormone control

• Glucose and insulin: as glucose increases it stimulates the pancreas to secrete insulin

Feedback control of insulin by glucose concentrations

Hormone-Receptor interactions

• Definition: a protein that binds a ligand with high affinity and low capacity. This binding must be saturuable.

• A tissue becomes a target for a hormone by expressing a specific receptor for it. Hormones circulate in the blood stream but only cells with receptors for it are targets for its action.

Agonist vs. Antagonist

• Agonists are molecules that bind the receptor and induce all the post-receptor events that lead to a biologic effect. In other words, they act like the "normal" hormone, although perhaps more or less potently

• Antagonists are molecules that bind the receptor and block binding of the agonist, but fail to trigger intracellular signaling events

Hormone-receptor interactions

• Hormone--receptor interaction is defined by an equilibrium constant called the Kd, or dissociation constant.

• The interaction is reversible and how easily the hormone is displaced from the receptor is a quantitation of its affinity.

• Hormone receptor interactions are very specific and the Kd ranges from 10-9 to 10-12 Molar

Spare receptors

• In most systems the maximum biological response is achieved at concentrations of hormone lower than required to occupy all of the receptors on the cell.

• Examples: – insulin stimulates maximum glucose oxidation in

adipocytes with only 2-3% of receptors bound– LH stimulates maximum testosterone production in Leydig

cells when only 1% of receptors are bound

Spare Receptors• Maximum response with 2-3% receptor occupancy• 97% of receptors are “spare”• Maximum biological response is achieved when all of

the receptors are occupied on an average of <3% of the time

• The greater the proportion of spare receptors, the more sensitive the target cell to the hormone

• Lower concentration of hormone required to achieve half-maximal response

Classes of hormones  

The hormones fall into two general classes based on their solubility in water. The water soluble hormones are the

catecholamines (epinephrine and norepinephrine) and peptide/protein hormones.

The lipid soluble hormones include thyroid hormone, steroid hormones and Vitamin D3

Types of receptors Receptors for the water soluble hormones are found

on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second

messenger systems which mediate the action of the hormone in the target cell.

Receptors for the lipid soluble hormones reside in the nucleus (and sometimes the cytoplasm) of the target cell. Because these hormones can diffuse through the lipid

bilayer of the plasma membrane, their receptors are located on the interior of the target cell

Hormones and their receptorsHormone Class of hormone Location

Amine (epinephrine) Water-soluble Cell surface

Amine (thyroid hormone)

Lipid soluble Intracellular

Peptide/protein Water soluble Cell surface

Steroids and Vitamin D Lipid Soluble Intracellular

Second messenger systems

Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell

Second messengers for cell-surface receptors

Second messenger systems include: Adenylate cyclase which catalyzes the conversion of ATP

to cyclic AMP; Guanylate cyclase which catalyzes the conversion of GMP

to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides);

Calcium and calmodulin; phospholipase C which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol.

Types of receptors

Second messenger systems Each of these second messenger systems activates a

specific protein kinase enzyme. These include cyclic nucleotide-dependent protein kinases Calcium/calmodulin-dependent protein kinase, and

protein kinase C which depends on diacyl glycerol binding for activation. Protein kinase C activity is further increased by calcium which is

released by the action of inositol phosphates.

Second messenger systems The generation of second messengers and activation

of specific protein kinases results in changes in the activity of the target cell which characterizes the response that the hormone evokes.

Changes evoked by the actions of second messengers are usually rapid

Signal transduction mechanisms of hormones

Activation of adenylate

cyclase

Inhibition of adenylate

cyclase

Increased phospho-inositide turnover

Tyrosine kinase activation

-adrenergic 2-adrenergic 1-adgrenergic Insulin

LH, FSH, TSH, hCG

Opioid Angiotensin II Growth factors (PDGF, EGF, FGF, IGF-1

Glucagon Muscarinic cholinergic – M2

Muscarinic cholinergic – M3

Growth hormone

Vasopressin- V2 Vasopressin –V1 Prolactin

ACTH

Cell surface receptor action

G-protein coupled receptorsAdenylate cyclase, cAMP and PKA

Amplification via 2nd

messenger

Transmembrane kinase-linked receptors

Certain receptors have intrinsic kinase activity. These include receptors for growth factors, insulin etc. Receptors for growth factors usually have intrinsic tyrosine kinase activity

Other tyrosine-kinase associated receptor, such as those for Growth Hormone, Prolactin and the cytokines, do not have intrinsic kinase activity, but activate soluble, intracellular kinases such as the Jak kinases.

In addition, a newly described class of receptors have intrinsic serine/threonine kinase activity—this class includes receptors for inhibin, activin, TGF, and Mullerian Inhibitory Factor (MIF).

Protein tyrosine kinase receptors

Receptors for lipid-soluble hormones reside within the cell

Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell.

The lipid soluble hormone diffuses into the cell and binds to the receptor which undergoes a conformational change. The receptor-hormone complex is then binds to specific DNA sequences called response elements.

These DNA sequences are in the regulatory regions of genes.

The receptor-hormone complex binds to the regulatory region of the gene and changes the expression of that gene.

In most cases binding of receptor-hormone complex to the gene stimulating the transcription of messenger RNA.

The messenger RNA travels to the cytoplasm where it is translated into protein. The translated proteins that are produced participate in the response that is evoked by the hormone in the target cell

Responses evoked by lipid soluble hormones are usually SLOW, requiring transcription/translation to evoke physiological responses.

Receptors for lipid-soluble hormones reside within the cell

Mechanism of lipid soluble hormone

action

Receptor control mechanisms• Hormonally induced negative regulation of receptors is

referred to as homologous-desensitization • This homeostatic mechanism protects from toxic effects of

hormone excess. • Heterologous desensitization occurs when exposure of the

cell to one agonist reduces the responsiveness of the cell any other agonist that acts through a different receptor.

• This most commonly occurs through receptors that act through the adenylyl cyclase system.

• Heterologous desensitization results in a broad pattern of refractoriness with slower onset than homologous desensitization