ENDOCRINOLOGY

• 1902; the “Hormone Theory”– Bayliss and Starling: Described first hormone

• Substance produced by small intestine–Stimulated flow of pancreatic juice:

called secretin• 1905; Starling introduced the term Hormone

– Greek: I arouse to activity or I excite

INTRODUCTION

Definition of HormoneHormone

– Substance released by one cell to regulate another cell. Synonymous with chemical messenger. Delivered through endocrine, neuroendocrine, neurocrine, paracrine, autocrine systems.

• Hormones can be: • Lipids (steroids, prostaglandins)• Proteins (FSH, TSH, GH)• Peptides (GnRH)• Amino Acids (catecholamines)

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.

Endocrine System

Helps to maintain homeostasis by Integration & control.

Secretion of chemical signals called hormones that travel through the bloodstream to act on target cells.

Endocrine vs Nervous system

Nervous system performs short term crisis managementEndocrine system regulates long term ongoing metabolic

Types of cell-to-cell signaling

Classic 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.

Response vs. distance traveled

Endocrine 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.

Endocrine System: OverviewEndocrine system – the body’s second great

controlling system which influences metabolic activities of cells by means of hormones.

A ductless gland composed of epithelial cells that releases secretions directly into extracellular fluid.

From the ECF the hormone diffuses into the bloodstream.

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

The Endocrine System

Types of Hormones

• Proteins and Polypeptides- Hormones from anterior and posterior pituitary , Pancreas, Parathyroid gland. These hormones are stored in secretory vesicles until needed .Usually released into blood stream via exocytosis .

• Steroid hormones : Hormones from adrenal cortex , ovaries and placenta .These hormones are usually synthesized from cholesterol and are not stored .

• Amine hormones : Thyroid and adrenal medullary hormones .They are derived from Tyrosine .

A Structural Classification of Hormones

Protein and Polypeptide Hormones: Synthesis and Release

Peptide/protein hormones

• 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

Amine hormones

There are two groups of hormones derived from the amino acid tyrosine

Thyroid 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

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

Hormones and their receptors

Hormone 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

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.

Hormones can be

• Freely circulating– Rapidly removed from bloodstream

• Bound to transport proteins

• Receptors for catecholamines, peptide hormones, eicosanoids are in the cell membranes of target cells.

• Thyroid and steroid hormones cross the membrane and bind to receptors in the cytoplasm or nucleus.

Mechanisms of hormone action

Types of receptors

G Proteins and Hormone Activity

Special kind of Receptor

•Tyrosine Kinases•In plasma membrance .•Integral proteins.•Receptor for insulin and growth factors.•Adds phosphate to amino acid tyrosine

Tyrosine Kinase (continued)

Hormone Effects on Gene Activity

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 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

Figure 17.3a

Neural Stimuli

• Neural stimuli – nerve fibers stimulate hormone release– Preganglionic sympathetic

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

Figure 17.3b

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

Figure 17.3c

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

Feedback control of hormone secretion

1) Negative feedback :Prevents over secretion of the hormone or over activity

at the target tissue.2) Positive feedback :There are two or more

variables ,if one increases the second one ,the second one in turn increases the first one or the 3rd one .E.g. Ovulation .

3) Cyclical Variations occur in hormone release

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

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

Circadian (chronotropic) control

Circadian Clock

HypothalamusRegulates the activity of the nervous and endocrine systems

Highest level of endocrine control 1)Secrets regulatory hormones that control the anterior pituitary gland2) Releases hormones at the posterior pituitary gland3) Exerts direct neural control over the endocrine cells of the adrenal medullae.

Hypothalamus• Located at the basal part of the diencephalon lying

below the thalamus• Split into left & right halves by the 3rd ventricle • Has many neuroendocrine, behavioural and

autonomic functions. Sexually dimorphic.– Sexual and ingestive behaviours– Control of body temperature– Integration of the cardiovascular & hormonal responses to

stress

Hypothalamus

• Within the hypothalamus there are many clusters of neurons hypothalamic nuclei – Supraoptic, paraventricular, arcuate, ventromedial &

suprachiasmatic – Medial anterior hypothalamic & medial preoptic areas

• These have either direct neural or indirect vascular connections to the pituitary gland

Parvocellular &MagnocellularNeurosecretoryNeurons

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Rostral Hyp

Medial Basal Hyp

Magnocellular System

• Magnocellular neurons are found in the supraoptic nuclei & paraventricular nuclei– Term “magno” means large– Axons from these neurons project to the posterior lobe of

the pituitary

• Oxytocin and ADH (vasopressin) are synthesized in the cell bodies of both nuclei. – During synthesis, they associate with the neurophysin, a

binding protein

Characteristics of hypothalamic releasing hormones

• Secretion in pulses• Act on specific membrane receptors• Transduce signals via second messengers• Stimulate release of stored pituitary hormones• Stimulate synthesis of pituitary hormones• Stimulates hyperplasia and hypertophy of target cells• Regulates its own receptor

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

Major Endocrine Organs: Pituitary (Hypophysis)

• 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– The secondary capillary plexus

Pituitary-Hypothalamic Relationships: Anterior Lobe

Pituitary gland

• Two parts of the pituitary are anatomically are functionally DIFFERENT.

• Adenohypophysis (anterior)– Derives from an inward invagination of the oral ectoderm

of the primitive mouth cavity known as Rathke’s pouch

• Neurohypophysis (posterior)– Arises from the neural ectoderm of the floor of the

forebrain

Anterior Lobe

• Contains a variety of cell types which secrete hormones

Posterior Lobe

• Contains no secretory cell bodies which synthesize hormones

• Composed of terminals of axons that originate in the hypothalamus

• Cell body of neuron secretes hormone which travels down to the end of the axon

• Posterior pituitary is ALL neural

Pituitary Hormones:a. Anterior pituitary (adenohypophysis)

1. Luteinizing hormone (LH)2. Follicle Stimulating Hormone (FSH)3. Thyroid Stimulating Hormone (TSH)4. Growth Hormone (Somatotropin; GH)5. Adrenocorticotropic Hormone (ACTH)6. Prolactin (Prl)

b. Posterior pituitary (neurohypophysis)OxytocinVasopressin (Antidiuretic Hormone; ADH)

c. Intermediate lobeMelanocyte Stimulating Hormone (MSH)

Anterior Pituitary Control• Hypothalamic control of anterior pituitary is very

different than for the posterior pituitary• AP is regulated by chemical factors or hormones

produced in the hypothalamus• Each anterior pituitary hormone probably has dual

hypothalamic hormones - one inhibits and one stimulates

• AP-regulating hormones travel from the hypothalamus to the anterior lobe by a specialized vascular route

Hypothalamic-pituitary portal system

• The specialized vascular route is termed the hypothalamic-pituitary portal system

• Portal system = two beds of capillaries connected by straight vessels

Figure 5.2.13 Feedback loops in a typical hypothalamo-hypophyseal axis. The target cell types (shaded area) may be any of those present in the anterior pituitary.

They operate in a closed-loop feedback mode to maintain relatively steady plasma levels of the hormones concerned, subject to modifications of the hypothalamic drive by inputs from outside the body (exteroceptive signals), or intrinsic to the brain (pulse-generator).

Long-loop and short-loop negative feedbacks involve respectively, the peripheral hormones and the tropic hormones.

Anterior pituitary hormones: Function

• ACTH and TSH stimulate other endocrine gland

• ACTH regulates the function of the adrenal cortex; increases release of adrenal steroids

• TSH regulates the function of the thyroid gland; increases release of thyroid hormones

Pituitary Hormone Actions:• FSH (secreted by gonadotrope cells)

– ovaries, stimulates development of eggs and follicles– testes, stimulates production of sperm

• LH (secreted by gonadotrope cells)– females, stimulates ovulation and corpus luteum to

secrete progesterone and estrogen– males, stimulates interstitial cells of testes to secrete

testosterone – One hypothalamic factor (gonadotropin-releasing

hormone – GnRH - decapeptide) stimulates the secretion of both hormones

Anterior pituitary hormones: Function of prolactin

• Prolactin is the major hormone responsible for milk production (lactogenesis) and also is part of the hormone complex that promotes growth/development of the mammary glands (mammogenesis).

• Blood levels of prolactin are low in non-pregnant, non-lactating females and in males.

• However, during pregnancy and lactation, blood levels of prolactin increase, consistent with the hormone's role in mammary gland development and lactogenesis.

• Essentially a hormone of reproduction. • Male, LH sensitivity in testes, thus testosterone secretion

(gonadotropic effect in males)

Control of prolactin

Prolactin secretion regulation • Stimuli which increase is :• After2 to 3 hours of onset of sleep and continues through

out the sleep• Exercise and stress• Pregnancy • Nursing and breast stimulation • Primary hypothyroidism • Dopamine antagonist like phenothiazine• Stimuli which decrease is :• Prolactin inhibitory factor (Dopamine)• Dopamine agonists: bromocriptine.

Maintenance of Lactation: Galactopoiesis

• Hormonal control & milk removal • Prolactin along with growth hormone,

glucocorticoids ,parathyroid hormone, and Insulin .

Prolactin (PRL): DisordersHyperprolactinemia • Hypersecretion due to adenohypophyseal tumors; Common

type of pituitary tumour (accounts for 60% of pituitary tumours). Other causes are due to primary hypothyroidism . The effects are due to associated decreased in FSH and LH levels

• Results in galactorrhea (inappropriate milk production), lack of menses and infertility in women; impotence in men.

• Treatment: Dopamine agonist: Bromocriptine .• Surgical removal of tumour .

Anterior pituitary hormones: Function of Growth Hormone

• GH is important to growth and the control of metabolic functions

• It acts directly on target cells which contain GH receptors

• And as importantly, indirectly via the secondary generation of growth factors (peptides) called somatomedins in the liver.

• There are at least two somatomedins (A and C. Somatomedins are also called insulin-like growth factors (IGF-1 and -2)

Metabolic Action of GH

Control of GH secretion

Growth Hormone Regulation

• Stimulation by:• Growth hormone releasing hormone ,Hypoglycemia,

Decrease in blood free fatty acids,Fasting,Exercise,Stress,Estrogens,Androgens, deep sleep.

• Inhibition by:• Somatostatin,Hyperglycemia,Rising free fatty

acids,somatomedins(IGF),GH,Cortisol,• Pregnancy, REM sleep .

Growth Hormone• Abnormalities

– Dwarfism: decreased secretion of hormone (prolonged steroid use) or decreased number of receptors (African pigmies)

– Gigantism: excess secretion occurs during aldolescence before epiphyseal plates close. up to 8’ tall, normal body proportions

– Acromegaly: excess secretion occurs during adulthood after epiphyseal plates close. Enlargement of extremities (hands and feet) and face, thickening of soft tissue.

Other Hormones Affecting Growth:Thyroid Hormones:

enhance GH effects and IGF production tissue sensitivity to GH

Insulin/Glucagon:

regulate metabolismInsulin: aa uptake into muscle and protein synthesis in bone matrix formation; GH/IGF receptors; IGF synthesis; vitamin D production

Gonadal Steroids: (cause epiphyseal closure)

Androgens - anabolic effects on muscle; GH secretionEstrogens - mechanism unclearosteoporosis in E2 deficiency

POSTERIOR PITUITARY• Hormones (ADH, oxytocin) synthesized in

hypothalamus• Travel down axons, stored in posterior pituitary• Released in response to increase frequency of action

potentials in same axons• Modified neurotransmitters• Whole system is nervous – cell bodies of neuron are

in hypothalamus, axons terminate in posterior pituitary.

Actions of ADH: Water retention

• ADH (vasopressin) has two actions, one on the kidney and the other on vascular smooth muscle. These actions are mediated by different receptors, different intracellular mechanisms, and different second messengers.

ADH: Increase in water permeability.

• The major action of ADH is to increase the water permeability of cells in the kidney distal tubule and collecting duct.

• The receptor for ADH on kidney cells is a V2 receptor, which is coupled to adenylyl cyclase via a Gs protein.

• The second messenger is cAMP, which, via phosphorylation steps, directs the insertion of water channels, aquaporin 2, into the kidney cell membranes.

• The increased water permeability of the cells allows more water to be reabsorbed by the collecting ducts (ie water moves from urine to blood) and makes the urine MORE concentrated or hyperosmotic.

ADH and contraction of vascular smooth muscle

• The second action of ADH is to cause contraction of vascular smooth muscle (as implied by its other name, vasopressin).

• The receptor for ADH on vascular smooth muscle is a V1 receptor, which is coupled to phospholipase C via a G protein.

• The second messenger for this action is an IP2/Ca cascade which produces contraction of vascular smooth muscle, constriction of arterioles, and increased total peripheral resistance.

Figure 5.2.10 Summary of the pathways involved in control of ADH secretion.

Factor affecting ADH secretion

ADH: Disorders

• Hyposecretion due to damage of hypothalamic nucleus or neurohypophysis diabetes insipidus - excessive urine production (polyuria) and thirst

• Hypersecretion SIADH (syndrome of inappropriate ADH secretion) – water retention, cerebral edema, headache,

weight gain, hypo-osmolarity

Diabetes Insipidus:

Central (lack of ADH secretion): Head injury or tumour

Nephrogenic (renal tubule insensitivity to ADH)

Polyuria (excessive watery urine) followed by polydypsia; thirst

Treatment :Analogues of ADH:Desmopressin (Nasal Spray)

Tumour: surgical removal of tumour

Actions of Oxytocin: Milk letdown

• Milk ejection. Prolactin stimulates lactogenesis. The milk is stored in mammary alveoli and small milk ducts.

• The major action of oxytocin is to cause milk letdown. When oxytocin is secreted in response to suckling or to conditioned responses, it causes contraction of myoepithelial cells lining these small ducts, forcing the milk into large ducts. The milk collects in cisterns and then flows out under pressure through the teat

Actions of Oxytocin: Uterine contractions

• Oxytocin causes powerful rhythmic contractions of primed uterine smooth muscle (myometrium).

• Oxytocin plays a role in parturition (the process of birth).

• Oxytocin can be used clinically to assist the birth process.

• Other actions :• Plays a role in sexual arousal and satisfaction in

males and nonlactating females.

Neuro-humeral reflex for OT

Anterior pituitary hormones