EndocrinologyEndocrinology

MODES OF HORMONE MODES OF HORMONE DELIVERY I:DELIVERY I:

ENDOCRINE: ENDOCRINE: Most common (classical) mode, Most common (classical) mode,

hormones delivered to target cells by hormones delivered to target cells by blood.blood.

PARACRINE: PARACRINE: Hormone released diffuses to its target Hormone released diffuses to its target

cells through immediate extracellular cells through immediate extracellular space. space.

Blood is not directly involved in the Blood is not directly involved in the delivery.delivery.

MODES OF HORMONE MODES OF HORMONE DELIVERY II:DELIVERY II:

NEUROENDOCRINE: NEUROENDOCRINE: Hormone is produced and released by a Hormone is produced and released by a

neuron, delivered to target cells by neuron, delivered to target cells by blood.blood.

AUTOCRINE: AUTOCRINE: Hormone released feeds-back on the Hormone released feeds-back on the

cell of origin, again without entering cell of origin, again without entering blood circulation.blood circulation.

Major endocrine glands in Major endocrine glands in the bodythe body

HORMONE-TARGET CELL HORMONE-TARGET CELL SPECIFICITYSPECIFICITY

Only target cells, or cells that have Only target cells, or cells that have specific receptors, will respond to specific receptors, will respond to the hormone’s presence. the hormone’s presence. The strength of this response will The strength of this response will

depend on:depend on: Blood levels of the hormoneBlood levels of the hormone The relative numbers of receptors for that The relative numbers of receptors for that

hormone on or in the target cellshormone on or in the target cells The affinity (or strength of interactions) of The affinity (or strength of interactions) of

the hormone and the receptor.the hormone and the receptor.

HALF-LIFE, ONSET, and HALF-LIFE, ONSET, and DURATION of HORMONE DURATION of HORMONE

ACTIVITYACTIVITY

The affinity of hormones to their The affinity of hormones to their specific receptors is typically very high specific receptors is typically very high

The actual concentration of a The actual concentration of a circulating hormone in blood at any circulating hormone in blood at any time reflects: time reflects: Its rate of release.Its rate of release. The speed of its inactivation and removal The speed of its inactivation and removal

from the body. from the body.

The half-life is the time required for the The half-life is the time required for the hormone to loose half of its original hormone to loose half of its original effectiveness (or drop to half of its original effectiveness (or drop to half of its original concentration.concentration.

The time required for hormone effects to The time required for hormone effects to take place varies greatly, from almost take place varies greatly, from almost immediate responses to hours or even days.immediate responses to hours or even days.

In addition, some hormones are produced in In addition, some hormones are produced in an inactive form and must be activated in an inactive form and must be activated in the target cells before exerting cellular the target cells before exerting cellular responses. responses.

In terms of the duration of hormone action, In terms of the duration of hormone action, it ranges from about 20 minutes to several it ranges from about 20 minutes to several hours, depending on the hormone. hours, depending on the hormone.

CONTROL OF HORMONE CONTROL OF HORMONE RELEASE:RELEASE:

The synthesis and secretion of most The synthesis and secretion of most hormones are usually regulated by hormones are usually regulated by negative feedback systemsnegative feedback systems..

As hormone levels rise, they stimulate As hormone levels rise, they stimulate target organ responses. These in turn, target organ responses. These in turn, inhibit further hormone release. inhibit further hormone release.

The stimuli that induce endocrine glands The stimuli that induce endocrine glands to synthesize and release hormones to synthesize and release hormones belong to one of the following major types:belong to one of the following major types: HumoralHumoral NeuralNeural Hormonal Hormonal

CHEMISTRY OF CHEMISTRY OF HORMONESHORMONES

Peptide hormonesPeptide hormones: largest, most complex, and most : largest, most complex, and most common hormones. Examples include insulin and common hormones. Examples include insulin and prolactinprolactin

Steroid hormonesSteroid hormones: lipid soluble molecules : lipid soluble molecules synthesized from cholesterol. Examples include synthesized from cholesterol. Examples include gonadal steroids (e.g testosterone and estrogen) gonadal steroids (e.g testosterone and estrogen) and adrenocortical steroids (e.g. cortisol and and adrenocortical steroids (e.g. cortisol and aldosterone).aldosterone).

AminesAmines: small molecules derived from individual : small molecules derived from individual amino acids. Include catecholamines (e.g. amino acids. Include catecholamines (e.g. epinephrine produced by the adrenal medulla), and epinephrine produced by the adrenal medulla), and thyroid hormones.thyroid hormones.

EicosanoidsEicosanoids: small molecules synthesized from fatty : small molecules synthesized from fatty acid substrates (e.g. arachidonic acid) located acid substrates (e.g. arachidonic acid) located within cell membraneswithin cell membranes

A A protein kinaseprotein kinase transfers the terminal transfers the terminal phosphate of ATP to a hydroxyl group on a phosphate of ATP to a hydroxyl group on a protein.protein.

A A protein phosphataseprotein phosphatase catalyzes removal catalyzes removal of the Pof the Pii by hydrolysis. by hydrolysis.

P r o te in O H + A T P P r o te in O P

O

O

O

+ A D P

P i H 2 O

P r o te in K in a s e

P r o te in P h o s p h a ta s e

Adenylate CyclaseAdenylate Cyclase (Adenylyl (Adenylyl Cyclase) catalyzes: Cyclase) catalyzes:  ATPATP cAMP + PPcAMP + PPii

Binding of certain Binding of certain hormoneshormones (e.g., epinephrine) to the (e.g., epinephrine) to the outer surface of a cell outer surface of a cell activates Adenylate Cyclase activates Adenylate Cyclase to form cAMP within the cell. to form cAMP within the cell.

Cyclic AMP is thus Cyclic AMP is thus considered to be a considered to be a second second messengermessenger..

N

N N

N

NH2

O

OHO

HH

H

H2C

HO

PO

O-

1'

3'

5' 4'

2'

cAMP

PhosphodiesterasePhosphodiesterase enzymes catalyze: enzymes catalyze:

cAMP + HcAMP + H22OO AMPAMP

The phosphodiesterase that The phosphodiesterase that cleaves cAMP is activated cleaves cAMP is activated by phosphorylation by phosphorylation catalyzed by Protein Kinase catalyzed by Protein Kinase A. A.

Thus Thus cAMP stimulates its cAMP stimulates its own degradationown degradation, leading , leading to rapid turnoff of a cAMP to rapid turnoff of a cAMP signal. signal.

N

N N

N

NH2

O

OHO

HH

H

H2C

HO

PO

O-

1'

3'

5' 4'

2'

cAMP

The subunit of a G-protein (G) binds GTP, & can hydrolyze it to GDP + Pi.

& subunits have covalently attached lipid anchors that bind a G-protein to the plasma membrane cytosolic surface.Adenylate Cyclase (AC) is a transmembrane protein, with cytosolic domains forming the catalytic site.

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PPi

cytosol

GDP GTP

A G-protein that is part of a pathway that stimulates Adenylate Cyclase is called Gs & its subunit Gs.

The The sequence of eventssequence of events by which a by which a hormone activates cAMP signaling:hormone activates cAMP signaling:

1. Initially 1. Initially GG has bound has bound GDPGDP, and , and & & subunitssubunits are complexed together. are complexed together.

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PPi

cytosol

GDP GTP

The complex of & subunits G

inhibits G.

2.2. Hormone bindingHormone binding to a 7-helix receptor (GPCR) to a 7-helix receptor (GPCR) causes a causes a conformational changeconformational change in the receptor in the receptor that is transmitted to the G protein. that is transmitted to the G protein.

The nucleotide-binding site on The nucleotide-binding site on GG becomes more becomes more accessible to the cytosol, where [GTP] > [GDP].accessible to the cytosol, where [GTP] > [GDP].

GG releases GDP & binds GTP (releases GDP & binds GTP (GDP-GTP exchangeGDP-GTP exchange). ).

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PPi

cytosol

GDP GTP

3.3. Substitution of Substitution of GTPGTP for GDP causes another for GDP causes another conformational change in conformational change in GG. .

GG-GTP-GTP dissociates from the inhibitory dissociates from the inhibitory complex complex & can now bind to and activate Adenylate Cyclase.& can now bind to and activate Adenylate Cyclase.

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PPi

cytosol

GDP GTP

4.4. Adenylate Cyclase Adenylate Cyclase, activated by, activated by GG-GTP, -GTP, catalyzes synthesis of catalyzes synthesis of cAMPcAMP..

5.5. Protein Kinase A Protein Kinase A (cAMP Dependent Protein (cAMP Dependent Protein Kinase) catalyzes phosphorylation of various Kinase) catalyzes phosphorylation of various cellular proteins, altering their activity.cellular proteins, altering their activity.

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PPi

cytosol

GDP GTP

Turn offTurn off of the signal: of the signal:

1.1. G G hydrolyzes GTP to GDP + P hydrolyzes GTP to GDP + Pii. . ((GTPaseGTPase).).

The presence of The presence of GDPGDP on G on G causes it to causes it to rebind to the inhibitory rebind to the inhibitory complex. complex.

Adenylate Cyclase is no longer activated.Adenylate Cyclase is no longer activated.

2. 2. PhosphodiesterasePhosphodiesterase catalyzes hydrolysis catalyzes hydrolysis of of cAMPcAMP AMPAMP..

Turn offTurn off of the signal (cont.): of the signal (cont.):

3. Hormone receptor 3. Hormone receptor desensitizationdesensitization occurs. occurs. This process varies with the hormone. This process varies with the hormone.

Some receptors are Some receptors are phosphorylatedphosphorylated via G- via G-protein-coupled receptor kinases. protein-coupled receptor kinases.

The phosphorylated receptor may then bind The phosphorylated receptor may then bind to a protein to a protein arrestinarrestin that blocks receptor- that blocks receptor-G-protein activation & promotes removal of G-protein activation & promotes removal of the receptor from the membrane by the receptor from the membrane by clathrin-mediated endocytosis. clathrin-mediated endocytosis.

4. 4. Protein PhosphataseProtein Phosphatase catalyzes removal by catalyzes removal by hydrolysis of phosphates that were attached to hydrolysis of phosphates that were attached to proteins via Protein Kinase A.proteins via Protein Kinase A.

PituitaryPituitary GlandGland

Pituitary development:Pituitary development:

The “Master The “Master Gland”Gland”

The pituitary has The pituitary has been called the been called the “Master” gland in “Master” gland in the body.the body.

This is because This is because most of the most of the pituitary hormones pituitary hormones control other control other endocrine glandsendocrine glands

Hormones of the anterior Hormones of the anterior pituitarypituitary

There are 6 main hormones which are secreted by There are 6 main hormones which are secreted by the adenohypophysis:the adenohypophysis:

1) Growth hormone (also known as somatotropin).1) Growth hormone (also known as somatotropin).

2) Thyroid-stimulating hormone (also known as 2) Thyroid-stimulating hormone (also known as thyrotropin).thyrotropin).

3) Adrenocorticotropic hormone (also known as 3) Adrenocorticotropic hormone (also known as corticotropin).corticotropin).

4) Prolactin.4) Prolactin.

5) Follicle-stimulating hormone.5) Follicle-stimulating hormone.

6) Luteinizing hormone.6) Luteinizing hormone.

Control of pituitary gland Control of pituitary gland secretionsecretion

Secretion of each hormone by the Secretion of each hormone by the adenohypophysis is controlled by adenohypophysis is controlled by neurohormones secreted by nerves in neurohormones secreted by nerves in the hypothalamus.the hypothalamus.

In most cases there are two In most cases there are two neurohormones controlling the neurohormones controlling the secretion of a pituitary hormone. One secretion of a pituitary hormone. One which stimulates pituitary secretion which stimulates pituitary secretion and one which inhibits pituitary and one which inhibits pituitary secretion. secretion.

Neurohormones:Neurohormones:

Are hormones secreted by nerve cells. Are hormones secreted by nerve cells. These are true hormones, since they These are true hormones, since they are secreted into the bloodstream.are secreted into the bloodstream.

All are secreted by neurosecretory All are secreted by neurosecretory neurons in the hypothalamus.neurons in the hypothalamus.

They are secreted into the hypophyseal They are secreted into the hypophyseal portal system, which then carries the portal system, which then carries the blood to the anterior pituitary.blood to the anterior pituitary.

Pituitary portal systemPituitary portal system Arterioles break into capillaries in the Arterioles break into capillaries in the

hypothalamus. hypothalamus. The axons of the neurosecretory cells form The axons of the neurosecretory cells form

plexuses with these capillaries. plexuses with these capillaries. Downstream, the capillaries combine into a vein Downstream, the capillaries combine into a vein

which carries the blood to the pars distalis. which carries the blood to the pars distalis. The vein breaks into a capillary network which The vein breaks into a capillary network which

supplies all the cells of the anterior lobe. supplies all the cells of the anterior lobe. Thus, the neurohormones are carried directly Thus, the neurohormones are carried directly

(well, sort of) from the hypothalamus to the (well, sort of) from the hypothalamus to the adenohypophysis. adenohypophysis.

Portal Portal systemsystem

Growth hormone (GH)Growth hormone (GH) Growth hormone is secreted by somatotrophs.Growth hormone is secreted by somatotrophs.

GH is a protein hormone consisting of a single GH is a protein hormone consisting of a single peptide chain of 191 amino acids. peptide chain of 191 amino acids.

GH secretion is stimulated by the secretion of GH secretion is stimulated by the secretion of GGrowth rowth HHormone ormone RReleasing eleasing HHormone (GHRH) by ormone (GHRH) by the hypothalamus.the hypothalamus.

GH secretion is inhibited by the secretion of GH secretion is inhibited by the secretion of somatostatin by the hypothalamus.somatostatin by the hypothalamus.

GH activates a tyrosine kinase receptor.GH activates a tyrosine kinase receptor.

Functions of GH:Functions of GH: GH has effects of every cell of the body, GH has effects of every cell of the body,

either directly or indirectly. Primarily, it either directly or indirectly. Primarily, it decreases the uptake and metabolism of decreases the uptake and metabolism of glucose. (Elevates plasma glucose)glucose. (Elevates plasma glucose)

Increases the breakdown of fat. (Increases Increases the breakdown of fat. (Increases the blood levels of fatty acids)the blood levels of fatty acids)

Increases the uptake of amino acids from Increases the uptake of amino acids from the blood and increases protein synthesis the blood and increases protein synthesis in cell. (Decreases plasma amino acids)in cell. (Decreases plasma amino acids)

Actions of GH on specific cell Actions of GH on specific cell types:types:

Muscle cells:Muscle cells:

Increases amino acid uptakeIncreases amino acid uptake Increases protein synthesisIncreases protein synthesis Decreases glucose uptakeDecreases glucose uptake

Net resultNet result: : Increased Increased Lean body massLean body mass

Chondrocytes:Chondrocytes:

increases uptake of sulfurincreases uptake of sulfur increases chondroitin sulfate productionincreases chondroitin sulfate production increases DNA, RNA synthesisincreases DNA, RNA synthesis increases Protein synthesisincreases Protein synthesis increases Amino acid uptakeincreases Amino acid uptake increases Collagen synthesisincreases Collagen synthesis increases Cell size and numberincreases Cell size and number

Net resultNet result: Increased : Increased Linear growthLinear growth

Hepatocytes:Hepatocytes:

Stimulates the production of Stimulates the production of somatomedins by the liver.somatomedins by the liver.

These somatomedins directly These somatomedins directly regulate metabolic function in target regulate metabolic function in target cells. They are also called insulin-cells. They are also called insulin-like growth factors, or IGFs. like growth factors, or IGFs.

Adipocytes:Adipocytes:

Decreases glucose uptakeDecreases glucose uptake Increases lypolysisIncreases lypolysis

Net resultNet result: Decreased : Decreased AdiposityAdiposity

Other cell types in general:Other cell types in general:

Increased protein synthesisIncreased protein synthesis Increased DNA, RNA synthesisIncreased DNA, RNA synthesis Increased cell size and numberIncreased cell size and number

Net result: Increased organ Net result: Increased organ sizesize

Increased organ Increased organ functionfunction

Other considerations:Other considerations:

GH has a short half-life of about 20 GH has a short half-life of about 20 minutes. However, the IGFs are minutes. However, the IGFs are much longer lived (Tmuch longer lived (T1/21/2 of about 20 of about 20 hours).hours).

GH and Insulin actions are GH and Insulin actions are correlated:correlated:

When there is ample dietary intake of proteins and When there is ample dietary intake of proteins and carbohydrates, then amino acids can be used for carbohydrates, then amino acids can be used for protein synthesis and growth.protein synthesis and growth.

Under these conditions, both insulin and GH Under these conditions, both insulin and GH secretion are stimulated.secretion are stimulated.

Net result:Net result: Amino acids are shunted to protein synthesis Amino acids are shunted to protein synthesis and glucose is shunted to metabolism.and glucose is shunted to metabolism.

However, under conditions where only However, under conditions where only carbohydrates are ingested, insulin secretion is carbohydrates are ingested, insulin secretion is increased, but GH secretion is decreased.increased, but GH secretion is decreased.

Net result: Net result: Both glucose AND amino acids are shunted to Both glucose AND amino acids are shunted to metabolism.metabolism.

Pathophysiology of abnormal Pathophysiology of abnormal GH secretion:GH secretion:

Hyposecretion:Hyposecretion:

Pre-adolescents: Pre-adolescents: Decreased GH secretion (or sensitivity) results Decreased GH secretion (or sensitivity) results

in slow growth and delayed onset of sexual in slow growth and delayed onset of sexual maturation. These children also tend to be maturation. These children also tend to be slightly chubby. slightly chubby.

Post-adolescents:Post-adolescents: Generally, no serious problems are associated Generally, no serious problems are associated

with hyposecretion of GH in mature individuals. with hyposecretion of GH in mature individuals. However, in very severe cases there can be However, in very severe cases there can be progeria (rapid and premature aging).progeria (rapid and premature aging).

Hypersecretion:Hypersecretion: Pre-adolescents: (before closure of Pre-adolescents: (before closure of

epiphyseal plates)epiphyseal plates)

Hypersecretion results in gigantism, Hypersecretion results in gigantism, where affected individuals grow where affected individuals grow extremely rapidly and become extremely rapidly and become abnormally tall (even over 2.4 m). Body abnormally tall (even over 2.4 m). Body proportions remain relatively normal. proportions remain relatively normal. Usually, there are cardiovascular Usually, there are cardiovascular complications later in life.complications later in life.

Post- adolescents: (after epiphyseal Post- adolescents: (after epiphyseal closure).closure).

Hypersecretion results in tissue Hypersecretion results in tissue enlargement. This is particularly true of enlargement. This is particularly true of the bones, which get heavier and the bones, which get heavier and thicker. They cannot elongate since the thicker. They cannot elongate since the epiphyseal plates are closed. A common epiphyseal plates are closed. A common symptom is a coarsening of the facial symptom is a coarsening of the facial features and enlargement of the hands features and enlargement of the hands and feet. This condition is known as and feet. This condition is known as acromegaly.acromegaly.

Treatments of GH secretion Treatments of GH secretion disorders:disorders:

Hypersecretion is usually caused by a Hypersecretion is usually caused by a tumour in the pituitary gland. tumour in the pituitary gland. Treatment consists of surgical or Treatment consists of surgical or radiation ablation of the tumour mass.radiation ablation of the tumour mass.

Hyposecretion is usually treated in Hyposecretion is usually treated in children by hormone replacement children by hormone replacement therapy. This is generally not required therapy. This is generally not required in adults, unless GH secretion is in adults, unless GH secretion is completely abolished.completely abolished.

Prolactin (PRL)Prolactin (PRL)

Structurally, very similar to growth Structurally, very similar to growth hormone (single peptide chain of 198 hormone (single peptide chain of 198 amino acids).amino acids).

PRL is secreted by mammotrophs PRL is secreted by mammotrophs (also referred to as lactotrophs).(also referred to as lactotrophs).

Secretion of PRL is also under dual Secretion of PRL is also under dual control by the hypothalamus.control by the hypothalamus.

Primarily under inhibitory control. This Primarily under inhibitory control. This means that if there is an injury to the means that if there is an injury to the hypophyseal portal system which blocks hypophyseal portal system which blocks hypothalamic regulation of the pituitary hypothalamic regulation of the pituitary gland, PRL levels increase. All other pituitary gland, PRL levels increase. All other pituitary hormone levels decrease when this happens.hormone levels decrease when this happens.

Dopamine is secreted by neuroendocrine Dopamine is secreted by neuroendocrine cells in the hypothalamus and inhibits PRL cells in the hypothalamus and inhibits PRL release.release.

PRL release is stimulated by thyrotropin PRL release is stimulated by thyrotropin releasing hormone (TRH), vasoactive releasing hormone (TRH), vasoactive intestinal peptide (VIP) and at least one intestinal peptide (VIP) and at least one other as yet unidentified factor.other as yet unidentified factor.

PRL activates a tyrosine kinase receptor.PRL activates a tyrosine kinase receptor.

Functions of PRL:Functions of PRL: In humans, the only effects of PRL so In humans, the only effects of PRL so

far identified are on reproduction far identified are on reproduction and nursing. and nursing.

PRL is important in stimulating PRL is important in stimulating differentiation of breast tissue during differentiation of breast tissue during development.development.

Stimulates further development of Stimulates further development of mammary glands during pregnancy.mammary glands during pregnancy.

Stimulates milk production (lactation) Stimulates milk production (lactation) after pregnancy.after pregnancy.

PRL has a role in regulation of the female PRL has a role in regulation of the female reproductive cycle. However, its precise reproductive cycle. However, its precise role has not be delineated yet. Excess role has not be delineated yet. Excess PRL secretion is know to block synthesis PRL secretion is know to block synthesis and release of gonadotropins, disrupting and release of gonadotropins, disrupting menstruation and causing infertility.menstruation and causing infertility.

PRL also can regulate male fertility, but PRL also can regulate male fertility, but how it does so remains unclear.how it does so remains unclear.

Pathophysiology of PRL Pathophysiology of PRL secretion:secretion:

Hyposecretion is never seen. However, Hyposecretion is never seen. However, hyperprolactinemia (excess secretion of hyperprolactinemia (excess secretion of PRL) is a fairly common disorder. Symptoms PRL) is a fairly common disorder. Symptoms in women usually include amenorrhea in women usually include amenorrhea (cessation of menstruation), galactorrhea (cessation of menstruation), galactorrhea (abnormal lactation) and infertility. In men, (abnormal lactation) and infertility. In men, infertility and galactorrhea are the most infertility and galactorrhea are the most common symptoms.common symptoms.

Treatment usually consists of administration Treatment usually consists of administration of a dopaminergic agonist, such as of a dopaminergic agonist, such as bromocriptine.bromocriptine.

Thyroid Stimulating Thyroid Stimulating hormone (TSH)hormone (TSH)

TSH is a glycoprotein hormone composed TSH is a glycoprotein hormone composed of 2 peptide chains a and b.of 2 peptide chains a and b.

The a subunit is called “unspecific” The a subunit is called “unspecific” because it is also incorporated into two because it is also incorporated into two other unrelated pituitary hormones (LH other unrelated pituitary hormones (LH and FSH).and FSH).

The b subunit contains the biologically The b subunit contains the biologically active sites. However, it must be active sites. However, it must be combined with the a subunit in order for combined with the a subunit in order for the hormone to be active.the hormone to be active.

TSH secretion is controlled very TSH secretion is controlled very tightly by the hypothalamus.tightly by the hypothalamus.

TSH secretion is stimulated by TSH secretion is stimulated by Thyrotropin-releasing hormone Thyrotropin-releasing hormone (TRH). TRH is a tripeptide, meaning (TRH). TRH is a tripeptide, meaning it is composed of three amino acids.it is composed of three amino acids.

TRH secretion is stimulated by TRH secretion is stimulated by thermal and caloric signals in the thermal and caloric signals in the brain.brain.

Control of TSH secretionControl of TSH secretion Negative control of TSH secretion Negative control of TSH secretion

occurs in two ways:occurs in two ways: Triiodothyronien or T3 (which will be Triiodothyronien or T3 (which will be

discussed later) feeds back on the discussed later) feeds back on the hypothalamus to stimulate secretion of hypothalamus to stimulate secretion of dopamine and somatostatin. These two dopamine and somatostatin. These two factors both function as TSH-release factors both function as TSH-release inhibiting factors.inhibiting factors.

T3 can feed back directly onto the T3 can feed back directly onto the thyrotrophs to directly inhibit TSH thyrotrophs to directly inhibit TSH secretion.secretion.

Function of TSH:Function of TSH:

TSH stimulates the follicular cells of the TSH stimulates the follicular cells of the thyroid to induce a number of responses:thyroid to induce a number of responses:

TSH activates both the cAMP and PIP TSH activates both the cAMP and PIP pathways: pathways: Increased cAMPIncreased cAMP Increased [CaIncreased [Ca2+2+]]ii

TSH can stimulate both cell growth (of TSH can stimulate both cell growth (of follicular cells) and secretion of Tfollicular cells) and secretion of T33 and and thyroxine ( Tthyroxine ( T44 ). ).

Adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH)(ACTH)

ACTH is a single peptide chain ACTH is a single peptide chain which is relatively small (30 amino which is relatively small (30 amino acids).acids).

ACTH secretion is primarily under ACTH secretion is primarily under stimulatory control (i.e. there isn’t stimulatory control (i.e. there isn’t an ACTH-release inhibitory factor).an ACTH-release inhibitory factor).

ACTH secretion is stimulated by ACTH secretion is stimulated by corticotropin releasing hormone (CRH).corticotropin releasing hormone (CRH).

CRH secretion can be stimulated by a CRH secretion can be stimulated by a large number of factors, most of which large number of factors, most of which would be considered stress factors.would be considered stress factors.

Examples; infection, trauma, sleep Examples; infection, trauma, sleep cycle, anxiety, depression and others. cycle, anxiety, depression and others. (Just remember stress).(Just remember stress).

Functions of ACTH:Functions of ACTH:

ACTH stimulates the adrenal gland to secrete ACTH stimulates the adrenal gland to secrete cortisol.cortisol.

ACTH levels are associated with the sleep cycle.ACTH levels are associated with the sleep cycle.

ACTH stimulates the cAMP pathway in ACTH stimulates the cAMP pathway in adrenocorticol cells.adrenocorticol cells.

ACTH can directly inhibit CRH secretion ACTH can directly inhibit CRH secretion (negative feedback).(negative feedback).

Follicular-Stimulating Follicular-Stimulating hormone (FSH)hormone (FSH)

Luteinizing Hormone (LH) Luteinizing Hormone (LH) These are generally grouped together and called These are generally grouped together and called

gonadotropines.gonadotropines.

Gonadotropins are secreted by the gonadotrophs, Gonadotropins are secreted by the gonadotrophs, which synthesize and secrete which synthesize and secrete bothboth LH and FSH. LH and FSH.

Both LH and FSH are peptide hormones.Both LH and FSH are peptide hormones.

Secretion of gonadotropins is mainly under positive Secretion of gonadotropins is mainly under positive control.control.

Hypothalamus secretes gonadotropin-releasing Hypothalamus secretes gonadotropin-releasing hormone (GnRH) which stimulates gonadotrophs to hormone (GnRH) which stimulates gonadotrophs to secrete both LH and FSH.secrete both LH and FSH.

Functions of LH and Functions of LH and FSH:FSH:

LH and FSH stimulate secretion of the sex steroids LH and FSH stimulate secretion of the sex steroids by the gonads. Mainly estrogen in women and by the gonads. Mainly estrogen in women and testosterone in men.testosterone in men.

FSH also stimulates gonadal release of inhibin, FSH also stimulates gonadal release of inhibin, which serves as a negative feedback factor to block which serves as a negative feedback factor to block release of FSH by pituitary.release of FSH by pituitary.

LH and FSH stimulate the gonadal release of LH and FSH stimulate the gonadal release of activin, which can have positive feedback on activin, which can have positive feedback on gonadotropin secretion by the pituitary.gonadotropin secretion by the pituitary.

Gonadal secretion of estrogen and testosterone can Gonadal secretion of estrogen and testosterone can negatively feedback on both the hypothalamus, to negatively feedback on both the hypothalamus, to reduce GnRH secretion, and the gonadotrophs reduce GnRH secretion, and the gonadotrophs directly, to reduce gonadotropin secretions.directly, to reduce gonadotropin secretions.

Hormones of the posterior Hormones of the posterior pituitary:pituitary:

Remember that the neurohypophysis serves as a Remember that the neurohypophysis serves as a storage organ for hormones produced by storage organ for hormones produced by neurosecretory cells in the hypothalamus.neurosecretory cells in the hypothalamus.

There are two hormones secreted by the There are two hormones secreted by the neurohypophysis:neurohypophysis: 1) antidiuretic hormone (ADH)1) antidiuretic hormone (ADH) 2) oxytocin2) oxytocin

Both hormones are peptide hormones containing Both hormones are peptide hormones containing 9 amino acid residues.9 amino acid residues.

They differ in only 2 amino acids, but have very They differ in only 2 amino acids, but have very different functions.different functions.

Both activate the PIP pathway in the target cells.Both activate the PIP pathway in the target cells.

ADHADH Term: diuresis ö means production of urine.Term: diuresis ö means production of urine.

ADH inhibits urine production, i.e. conserves water ADH inhibits urine production, i.e. conserves water in the body.in the body.

Main target for ADH are the cells in the kidney Main target for ADH are the cells in the kidney which reabsorb water (will be covered in detail in which reabsorb water (will be covered in detail in the section on renal physiology).the section on renal physiology).

ADH secretion is stimulated by either an increase ADH secretion is stimulated by either an increase in the osmotic concentration of the blood, or by a in the osmotic concentration of the blood, or by a decrease in blood volumedecrease in blood volume usually sensed by a decrease in blood pressure.usually sensed by a decrease in blood pressure.

Secretion of ADH causes retention of water, Secretion of ADH causes retention of water, which will tend to counteract both an which will tend to counteract both an increase in blood concentration and/or increase in blood concentration and/or decrease in blood volume.decrease in blood volume.

cannot overcome serious blood loss.cannot overcome serious blood loss.

Conversely, excess consumption of water Conversely, excess consumption of water will have two effects:will have two effects: increase blood volume (and pressure).increase blood volume (and pressure). decrease blood concentration.decrease blood concentration.

Under these conditions ADH secretion is Under these conditions ADH secretion is inhibited.inhibited.

This results in formation of This results in formation of more more urine, which is urine, which is usually fairly dilute.usually fairly dilute.

Blood loses water and thus volume.Blood loses water and thus volume.

OxytocinOxytocin Release of oxytocin is under neural Release of oxytocin is under neural

control (like with ADH).control (like with ADH).

However, unlike ADH, the release of However, unlike ADH, the release of oxytocin is largely controlled by oxytocin is largely controlled by emotional state.emotional state.

Oxytocin specifically stimulates certain Oxytocin specifically stimulates certain smooth muscles to contract.smooth muscles to contract.

Primarily those of the reproductive tract Primarily those of the reproductive tract and mammary glands.and mammary glands.

Oxytocin is required for nursing.Oxytocin is required for nursing.

Principally know as the “milk letdown Principally know as the “milk letdown factor”.factor”.

It is secreted within seconds of the onset It is secreted within seconds of the onset of suckling.of suckling. Sensory receptors in the nipples generate Sensory receptors in the nipples generate

afferent impulses that stimulate the afferent impulses that stimulate the hypothalamus, triggering oxytocin secretion.hypothalamus, triggering oxytocin secretion.

Can actually be secreted in response to Can actually be secreted in response to auditory input, auditory input, i.ei.e. in nursing mothers in . in nursing mothers in response to hearing their babies cry.response to hearing their babies cry.

Effects of OxytocinEffects of Oxytocin

Oxytocin stimulation at low doses Oxytocin stimulation at low doses causes rhythmic contractions of the causes rhythmic contractions of the uterus.uterus.

Oxytocin stimulation at high dose causes Oxytocin stimulation at high dose causes sustained tetanic uterine contractions.sustained tetanic uterine contractions.

Oxytocin is often used to induce labour.Oxytocin is often used to induce labour.

It is now generally believed that oxytocin It is now generally believed that oxytocin believed that oxytocin produced by the believed that oxytocin produced by the fetus plays a critical role in labour.fetus plays a critical role in labour.

Oxytocin is also used to stop post-partum Oxytocin is also used to stop post-partum bleeding.bleeding.

The number of oxytocin receptors in The number of oxytocin receptors in uterine smooth muscles increases towards uterine smooth muscles increases towards the end of pregnancy.the end of pregnancy.

Oxytocin affects smooth muscle cells in Oxytocin affects smooth muscle cells in uterus and vagina of non-pregnant women.uterus and vagina of non-pregnant women.

There is clear evidence that oxytocin is There is clear evidence that oxytocin is involved in sexual arousal and orgasm in involved in sexual arousal and orgasm in both men and women.both men and women.

What role it plays in men is unknown. However, What role it plays in men is unknown. However, it may play a strong role in reinforcing the pair-it may play a strong role in reinforcing the pair-bond.bond.

The role in women is only slightly better The role in women is only slightly better known.known.

Oxytocin is secreted in response to vaginal Oxytocin is secreted in response to vaginal distention during intercourse.distention during intercourse.

Oxytocin is also secreted in response to Oxytocin is also secreted in response to stimulation of the nipples.stimulation of the nipples.

Emotional considerationsEmotional considerations

Oxytocin secretion during sexual Oxytocin secretion during sexual intercourse probably serves to intercourse probably serves to reinforce the male-female pair-bond.reinforce the male-female pair-bond.

Often referred to as the “the cuddle Often referred to as the “the cuddle hormone” or “the love hormone” in the hormone” or “the love hormone” in the popular press.popular press.

Secretion of oxytocin during and Secretion of oxytocin during and after labour may play an important after labour may play an important role in the formation of the mother-role in the formation of the mother-child pair-bond.child pair-bond.

Oxytocin secreted during suckling may Oxytocin secreted during suckling may serve to reinforce this pair-bond.serve to reinforce this pair-bond.

Recent studies with knock out mice Recent studies with knock out mice has shown that oxytocin is critical in has shown that oxytocin is critical in initiating and maintaining maternal initiating and maintaining maternal care.care.

Oxytocin secreted in response to Oxytocin secreted in response to suckling can cause uterine contractions suckling can cause uterine contractions which may play a role in the recovery of which may play a role in the recovery of uterine muscle tone after pregnancy and uterine muscle tone after pregnancy and may serve to shrink the uterus back to may serve to shrink the uterus back to normal.normal.

Thyroid Gland:Thyroid Gland: Location and StructureLocation and Structure

The largest pure endocrine gland in the The largest pure endocrine gland in the body, located in the front of the neck, body, located in the front of the neck, on the trachea just below to the larynx.on the trachea just below to the larynx.

Its two lobes are connected by a median Its two lobes are connected by a median tissue mass called the isthmus. tissue mass called the isthmus.

Internally, it is composed of about 1 Internally, it is composed of about 1 million of round million of round folliclesfollicles. The walls of . The walls of each follice are formed by cuboidal and each follice are formed by cuboidal and squamous epithelial cells called follicle squamous epithelial cells called follicle cells, which produce cells, which produce thyroglobulinthyroglobulin (glycoprotein). (glycoprotein).

The lumen of each follicle stores The lumen of each follicle stores colloidcolloid, which consists primarily of , which consists primarily of molecules of thyroglobulin.molecules of thyroglobulin.

The follicular epithelium also consists The follicular epithelium also consists of parafollicular cells, a separate of parafollicular cells, a separate population of endocrine cells that population of endocrine cells that produce calcitonin, a hormone produce calcitonin, a hormone involved in calcium homeostasis.involved in calcium homeostasis.

Thyroid hormones (THs)Thyroid hormones (THs) The two THs contain iodine and are called The two THs contain iodine and are called

thyroxin or Tthyroxin or T44 and triiodothyronine or T and triiodothyronine or T33. .

TT44 and T and T33 have a very similar structure as each have a very similar structure as each is made up of two tyrosine amino acids linked is made up of two tyrosine amino acids linked together and either 4 or 3 atoms of iodine, together and either 4 or 3 atoms of iodine, respectively.respectively.

TT44 is the main hormone produced by the is the main hormone produced by the thyroid and Tthyroid and T33 has most if not all of biological has most if not all of biological activity as all target tissues rapidly convert Tactivity as all target tissues rapidly convert T44 to Tto T33..

Except for the adult brain, spleen, testes, and Except for the adult brain, spleen, testes, and the thyroid gland itself, THs affect all other types the thyroid gland itself, THs affect all other types of cells in the body where they stimulate activity of cells in the body where they stimulate activity of enzymes especially those involved in glucose of enzymes especially those involved in glucose metabolismmetabolism

Increase metabolic rate in target tissues, which Increase metabolic rate in target tissues, which increases body heat production (calorigenic increases body heat production (calorigenic effect).effect).

THs also are critically important for normal THs also are critically important for normal growth and development of skeletal and nervous growth and development of skeletal and nervous systems and maturation of reproductive system.systems and maturation of reproductive system.

Synthesis of thyroid Synthesis of thyroid hormones:hormones:

Formation and storage of Formation and storage of thyroglobulin. thyroglobulin.

This process takes place in follicle cells This process takes place in follicle cells and the final product is packed into and the final product is packed into vesicles, their contents are discharged vesicles, their contents are discharged into the lumen of the follicle and into the lumen of the follicle and become a major part of the colloid.become a major part of the colloid.

Iodide trapping and oxidation to Iodide trapping and oxidation to iodine. iodine.

To produce functional iodinated To produce functional iodinated hormones, follicle cells accumulate hormones, follicle cells accumulate iodide from the blood. A protein pump iodide from the blood. A protein pump (iodide trap), located on the basal (iodide trap), located on the basal surface of follicle cells, actively surface of follicle cells, actively transports iodide into follicle cells transports iodide into follicle cells where it is oxidized and converted to where it is oxidized and converted to iodine (Iiodine (I22).).

Iodination. Iodination.

Once formed, iodine is attached to Once formed, iodine is attached to tyrosine amino acids which are part of tyrosine amino acids which are part of the thyroglobulin.the thyroglobulin.

Iodination of one tyrosine produces Iodination of one tyrosine produces monoiodotyrosine (MIT), iodination of monoiodotyrosine (MIT), iodination of two tyrosines diiodotyrosine (DIT). two tyrosines diiodotyrosine (DIT).

Coupling. Coupling.

Then enzymes within the colloid link Then enzymes within the colloid link MITs and DITs in a highly specific MITs and DITs in a highly specific fashion, as a result two DITs linked fashion, as a result two DITs linked together result in T4 , while coupling of together result in T4 , while coupling of MIT and DIT produce T3. MIT and DIT produce T3.

Coupling (cont.) Coupling (cont.)

Interactions between two DITs are more Interactions between two DITs are more frequent so more thyroxin. frequent so more thyroxin.

At this point both thyroid hormones are At this point both thyroid hormones are still attached to thyroglobulin molecules still attached to thyroglobulin molecules in the colloid.in the colloid.

Colloid endocytosis. Colloid endocytosis.

Colloid droplets containing iodinated Colloid droplets containing iodinated thyroglobulin are taken up by follicle thyroglobulin are taken up by follicle cells by endocytosis. These combine cells by endocytosis. These combine with lysosomes to form with lysosomes to form phagolysosomes.phagolysosomes.

Cleavage of the hormones for Cleavage of the hormones for release. release.

Within the phagolysosomes, the Within the phagolysosomes, the hormones are cleaved from the hormones are cleaved from the thyroglobulin by lysosomal enzymes. thyroglobulin by lysosomal enzymes. The free hormones then diffuse through The free hormones then diffuse through the basal membrane out of the follicle the basal membrane out of the follicle cell and into the blood stream.cell and into the blood stream.

Transport and regulation of Transport and regulation of release:release:

Most released TMost released T44 and T and T33 immediately bind to immediately bind to plasma proteins, of which the most important is plasma proteins, of which the most important is thyroxin-binding globulin (TBG) produced by the thyroxin-binding globulin (TBG) produced by the liver. liver.

Binding proteins protect TBinding proteins protect T44 and T and T33 from immediate from immediate degeneration by plasma enzymes, also they allow degeneration by plasma enzymes, also they allow TT44 and T and T33 to reach target tissues, often located a to reach target tissues, often located a significant distance away from the thyroid gland. significant distance away from the thyroid gland.

Decreasing blood levels of thyroxin trigger release Decreasing blood levels of thyroxin trigger release of TSH from the anterior pituitary, which of TSH from the anterior pituitary, which stimulates the thyroid gland to produce more stimulates the thyroid gland to produce more thyroxin.thyroxin.

Pathology of the thyroid gland Pathology of the thyroid gland function:function:

Both hypo- and hyperactivity and of the thyroid Both hypo- and hyperactivity and of the thyroid gland can cause severe metabolic disturbances. gland can cause severe metabolic disturbances.

In adults, hypothyroidism is referred to asIn adults, hypothyroidism is referred to as myxedema. myxedema.

Symptoms: Symptoms:

Low metabolic rate, poor resistance to cold Low metabolic rate, poor resistance to cold temperatures, constipation, dry skin (especially facial), temperatures, constipation, dry skin (especially facial), puffy eyes, lethargy and mental sluggishness. puffy eyes, lethargy and mental sluggishness.

If hypothyroidism results from lack of iodine the If hypothyroidism results from lack of iodine the thyroid gland enlarges to form a thyroid gland enlarges to form a goitergoiter..

Severe hypothyroidism during the fetal development and in infants is called cretinism.

Symptoms: A short disproportionate body, a thick

tongue and neck, and mental retardation. The condition is preventable by thyroid

hormone replacement therapy. However, once developmental abnormalities and mental retardation appear, they are not reversible.

Hyperthyroidism:Hyperthyroidism:

The most common form of hyperthyroidism is Grave's disease, The most common form of hyperthyroidism is Grave's disease, believed to be an autoimmune disease. believed to be an autoimmune disease.

The immune system produces antibodies that mimic TSH, The immune system produces antibodies that mimic TSH, which bind to TSH receptors and permanently switch them on, which bind to TSH receptors and permanently switch them on, resulting in continuous release of thyroid hormones. resulting in continuous release of thyroid hormones.

Typical symptoms include metabolic rate, sweating, rapid and Typical symptoms include metabolic rate, sweating, rapid and irregular heartbeat, nervousness, and weight loss despite irregular heartbeat, nervousness, and weight loss despite adequate food intake. adequate food intake.

Often, exophthalmos, or protrusion of the eyeballs, occurs Often, exophthalmos, or protrusion of the eyeballs, occurs caused by the edema of tissues behind the eyes followed by caused by the edema of tissues behind the eyes followed by fibrosis. fibrosis.

Treatments include surgical removal of the thyroid gland (very Treatments include surgical removal of the thyroid gland (very difficult due to an extremely rich blood supply) or ingestion of difficult due to an extremely rich blood supply) or ingestion of radioactive iodine (radioactive iodine (131131I), which selectively destroys the most I), which selectively destroys the most active thyroid cells.active thyroid cells.

Hyperthyroidism and Grave’s Hyperthyroidism and Grave’s DiseaseDisease

Parathyroid Glands:Parathyroid Glands:

The parathyroid The parathyroid glands are small in glands are small in size and are found size and are found on the posterior on the posterior aspect of the thyroid aspect of the thyroid gland. gland.

Typically, there are Typically, there are four of them but the four of them but the actual number may actual number may vary. vary.

Histology of the Histology of the ParathyroidParathyroid

The endocrine The endocrine cells within these cells within these glands are glands are arranged in thick, arranged in thick, branching cords branching cords containing containing oxyphil cells of oxyphil cells of unclear function unclear function and most and most importantly large importantly large numbers of numbers of chief chief cellscells that secrete that secrete parathyroid parathyroid hormone (PTH)hormone (PTH)..

PTH:PTH: Small proteinSmall protein

Single most important hormone controlling Single most important hormone controlling calcium homeostasis. Its release is calcium homeostasis. Its release is triggered by falling blood calcium levels triggered by falling blood calcium levels and inhibited by hypercalcemia (high blood and inhibited by hypercalcemia (high blood calcium). calcium).

There are three target organs for PTH:There are three target organs for PTH:

skeletonskeleton kidneyskidneys intestineintestine

PTH stimulates the PTH stimulates the following on these target following on these target

organs:organs: Osteoclasts (bone absorbing cells) are stimulated to Osteoclasts (bone absorbing cells) are stimulated to

digest bone and release ionic calcium and phosphates digest bone and release ionic calcium and phosphates to the blood.to the blood.

Kidneys are stimulated to reabsorb calcium and Kidneys are stimulated to reabsorb calcium and excrete phosphate.excrete phosphate.

Intestines are stimulated to increase calcium Intestines are stimulated to increase calcium absorption. absorption.

Vitamin D is required for absorption of calcium from Vitamin D is required for absorption of calcium from ingested food. ingested food. For vitamin D to exert this effect, it must first be converted For vitamin D to exert this effect, it must first be converted

by the kidneys to its active formby the kidneys to its active form It is this conversion that is directly stimulated by PTH.It is this conversion that is directly stimulated by PTH.

Pathology of the Pathology of the parathyroid glands:parathyroid glands:

Because calcium is essential for so Because calcium is essential for so many functions, including transmission many functions, including transmission of action potentials, muscle of action potentials, muscle contraction, pacemaker activity in the contraction, pacemaker activity in the heart, and blood clotting, precise heart, and blood clotting, precise control of ionic calcium levels in body control of ionic calcium levels in body fluids is absolutely critical. As a result fluids is absolutely critical. As a result both hyper- and hypoparathyroidism both hyper- and hypoparathyroidism can have severe consequences.can have severe consequences.

Hyperparathyroidism:Hyperparathyroidism: Rare, usually the result of a parathyroid gland tumor.Rare, usually the result of a parathyroid gland tumor.

Results in severe loss of calcium from the bones. Results in severe loss of calcium from the bones.

The bones soften and deform as their mineral salts The bones soften and deform as their mineral salts are replaced by fibrous connective tissue. are replaced by fibrous connective tissue.

Results in hypercalcemia Results in hypercalcemia

Leads to, depression of the nervous system leading to Leads to, depression of the nervous system leading to abnormal reflexes and weakness of the skeletal muscles, and abnormal reflexes and weakness of the skeletal muscles, and formation of kidney stones as excess calcium salts are formation of kidney stones as excess calcium salts are deposited in kidney tubules.deposited in kidney tubules.

Hypoparathyroidism:Hypoparathyroidism:

It is a PTH deficiency, which is a common It is a PTH deficiency, which is a common consequence of parathyroid trauma or consequence of parathyroid trauma or removal during thyroid surgery. removal during thyroid surgery.

The resulting hypocalcemia increases The resulting hypocalcemia increases excitability of neurons and may lead to excitability of neurons and may lead to tetany resulting in uncontrollable muscle tetany resulting in uncontrollable muscle twitches and convulsions, which if twitches and convulsions, which if untreated may progress to spasms of the untreated may progress to spasms of the larynx, respiratory paralysis and death.larynx, respiratory paralysis and death.

ADRENAL GLANDS:ADRENAL GLANDS:

The two adrenal The two adrenal glands are pyramid-glands are pyramid-shaped organs shaped organs found atop the found atop the kidneys.kidneys.

Each gland is Each gland is structurally and structurally and functionally two functionally two endocrine glands in endocrine glands in one.one.

The inner adrenal medulla is made up of nervous tissue and acts as part of the sympathetic nervous system. The outer adrenal cortex forms the bulk (about 80%) of the gland. Each of these regions produces its own set of hormones.

Adrenal Medulla:Adrenal Medulla: It is made up of chromaffin cells which secrete the It is made up of chromaffin cells which secrete the

catecholamines epinephrine (E) (adrenaline) and catecholamines epinephrine (E) (adrenaline) and norepinephrine (NE) (noradrenaline) into the blood. norepinephrine (NE) (noradrenaline) into the blood.

During the fight-or-flight responses, the sympathetic During the fight-or-flight responses, the sympathetic nervous system is activated, including the chromaffin nervous system is activated, including the chromaffin tissue and large amounts of catecholamines (80% of which tissue and large amounts of catecholamines (80% of which is E) are released.is E) are released.

In most cases the two hormones have very similar effects In most cases the two hormones have very similar effects on their target organs. However, E is the more potent on their target organs. However, E is the more potent stimulator of the heart rate and strength of contraction, stimulator of the heart rate and strength of contraction, and metabolic activities, such as breakdown of glycogen and metabolic activities, such as breakdown of glycogen and release of glucose).and release of glucose).

NE has great effect on peripheral vasoconstriction and NE has great effect on peripheral vasoconstriction and blood pressure.blood pressure.

Adrenal Cortex:Adrenal Cortex:

The cells of the adrenal cortex are The cells of the adrenal cortex are arranged in three distinct zones, each zone arranged in three distinct zones, each zone producing corticosteroids.producing corticosteroids.

The The Zona glomerulosaZona glomerulosa is the outer-most is the outer-most layer of cells and it produces layer of cells and it produces mineralocorticoids, that help control the mineralocorticoids, that help control the balance of minerals and water in the blood. balance of minerals and water in the blood.

The The zona fasciculatazona fasciculata is composed of cells is composed of cells that secrete glucocorticoids. that secrete glucocorticoids.

The The zona reticulariszona reticularis produce small produce small amounts of adrenal sex steroids.amounts of adrenal sex steroids.

Hormones of the Adrenal Hormones of the Adrenal CortexCortex MineralocorticoidsMineralocorticoids

Although there are several Although there are several mineralocorticoids, mineralocorticoids, aldosteronealdosterone is by far the is by far the most potent and accounts for more than 95% most potent and accounts for more than 95% of production. Its main function is to maintain of production. Its main function is to maintain sodium balance by reducing excretion of this sodium balance by reducing excretion of this ion from the body. ion from the body.

The primary target organs of aldosterone are The primary target organs of aldosterone are kidney tubules where it stimulates kidney tubules where it stimulates reabsorption of sodium ions from urine back reabsorption of sodium ions from urine back to the bloodstream. to the bloodstream.

Aldosterone also enhances sodium absorption Aldosterone also enhances sodium absorption from sweat, saliva, and gastric juice. from sweat, saliva, and gastric juice.

Secretion of aldosterone is induced by a Secretion of aldosterone is induced by a number of factors such as high blood levels number of factors such as high blood levels of potassium, low blood levels of sodium, and of potassium, low blood levels of sodium, and decreasing blood volume and pressure. decreasing blood volume and pressure.

The reverse conditions inhibit secretion of The reverse conditions inhibit secretion of aldosterone. aldosterone.

Glucocorticoids:Glucocorticoids:

Glucocorticoids influence metabolism of most Glucocorticoids influence metabolism of most body cells, help us resist stress, and are body cells, help us resist stress, and are considered to be absolutely essential to life. considered to be absolutely essential to life.

The most important glucocorticoid in humans is The most important glucocorticoid in humans is cortisolcortisol, , but small amounts of cortisone and corticosterone are but small amounts of cortisone and corticosterone are also produced.also produced.

The main effect of cortisol is to promote gluconeogenesis The main effect of cortisol is to promote gluconeogenesis or formation of glucose from noncarbohydrate or formation of glucose from noncarbohydrate molecules, especially fats and proteins. molecules, especially fats and proteins.

Cortisol also breaks down adipose (fat) tissue, released Cortisol also breaks down adipose (fat) tissue, released fatty acids can be then used by many tissues as a source fatty acids can be then used by many tissues as a source of energy and "saving" glucose for the brain. of energy and "saving" glucose for the brain.

Blood levels of glucocorticoids increase significantly Blood levels of glucocorticoids increase significantly during stress, which helps the body to negotiate the during stress, which helps the body to negotiate the crisis.crisis.

Interestingly, chronic excess of cortisol has significant Interestingly, chronic excess of cortisol has significant anti-inflammatory and anti-immune effects and anti-inflammatory and anti-immune effects and glucocorticoid drugs are often used to control symptoms glucocorticoid drugs are often used to control symptoms of many chronic inflammatory disorders, such as of many chronic inflammatory disorders, such as rheumatoid arthritis or allergic responses.rheumatoid arthritis or allergic responses.

Regulation of glucocorticoid Regulation of glucocorticoid secretion:secretion:

It is provided by a typical negative feedback It is provided by a typical negative feedback system:system:

increased (hypothalamus) CRH increased (hypothalamus) CRH negativenegative

increased (adenohypophysis) ACTH increased (adenohypophysis) ACTH increased (adrenal cortex) cortisolincreased (adrenal cortex) cortisol

Gonadocorticoids (Sex Hormones)Gonadocorticoids (Sex Hormones)

The amount of sex steroids produced by The amount of sex steroids produced by zona reticularis is insignificant compared zona reticularis is insignificant compared to the amounts secreted by the gonads. to the amounts secreted by the gonads.

These hormones may contribute to the These hormones may contribute to the onset of puberty and the appearance of onset of puberty and the appearance of axillary and pubic hair in both males and axillary and pubic hair in both males and females. females.

In adult women adrenal In adult women adrenal androgens androgens (male (male sex hormones, especially testosterone) may sex hormones, especially testosterone) may be, at least partially, responsible for the sex be, at least partially, responsible for the sex drive.drive.

Pathology of the adrenal cortex Pathology of the adrenal cortex functionfunction:

Hyperadrenalism :Hyperadrenalism : It is referred to as Cushing's disease and can be It is referred to as Cushing's disease and can be

caused by a cortisol-secreting tumour in the caused by a cortisol-secreting tumour in the adrenal glands, ACTH-secreting tumour of the adrenal glands, ACTH-secreting tumour of the pituitary, or ACTH secreted by abdominal pituitary, or ACTH secreted by abdominal carcinoma. carcinoma.

However, it most often results from the clinical However, it most often results from the clinical administration of pharmacological (very high) administration of pharmacological (very high) doses of glucocorticoid drugs. doses of glucocorticoid drugs.

The symptoms include a persistent The symptoms include a persistent hyperglycaemia, dramatic loss of muscle and bone hyperglycaemia, dramatic loss of muscle and bone proteins, and water and salt retention, leading to proteins, and water and salt retention, leading to hypertension and edema - one of its signs is a hypertension and edema - one of its signs is a swollen "moon" face. The only treatment is a swollen "moon" face. The only treatment is a surgical removal of tumour or discontinuation of surgical removal of tumour or discontinuation of the drug.the drug.

Hypoadrenalism :Hypoadrenalism :

It is referred to as Addison's disease It is referred to as Addison's disease and involves significant reduction in and involves significant reduction in plasma glucose and sodium, very high plasma glucose and sodium, very high levels of potassium and loss of weight. levels of potassium and loss of weight. The usual treatment is corticosteroid The usual treatment is corticosteroid replacement therapy.replacement therapy.

THE ENDOCRINE THE ENDOCRINE PANCREAS:PANCREAS:

Located partially behind the stomach, Located partially behind the stomach, the pancreas is a mixed gland composed the pancreas is a mixed gland composed of both endocrine and exocrine cells. of both endocrine and exocrine cells.

More than 98% of the gland is made up More than 98% of the gland is made up of acinar cells producing an enzyme-rich of acinar cells producing an enzyme-rich juice that enters a system of ducts and juice that enters a system of ducts and is delivered to the duodenum of the is delivered to the duodenum of the small intestine during food digestion. small intestine during food digestion.

The remaining 1-2% of cells form about The remaining 1-2% of cells form about 1 million of islets of Langerhans, tiny 1 million of islets of Langerhans, tiny cell clusters that produce pancreatic cell clusters that produce pancreatic hormones. hormones.

The islets have four distinct populations The islets have four distinct populations of cells, the two most important ones are of cells, the two most important ones are alpha cells that produce hormone alpha cells that produce hormone glucagon, and more numerous beta cells glucagon, and more numerous beta cells that synthesize insulin. In addition, delta that synthesize insulin. In addition, delta cells produce somatostatin and F cells cells produce somatostatin and F cells secrete pancreatic polypeptide (PP). secrete pancreatic polypeptide (PP).

Hormones of the Hormones of the Pancreas:Pancreas: Glucagon and insulin are directly responsible for the Glucagon and insulin are directly responsible for the

regulation of blood glucose levels and their effects regulation of blood glucose levels and their effects are exactly opposite: are exactly opposite:

insulin is hypoglycemic (it decreases blood glucose)insulin is hypoglycemic (it decreases blood glucose)

glucagon is hyperglycemic (it increases blood glucagon is hyperglycemic (it increases blood glucose). glucose).

Pancreatic somatostatin inhibits the release of both Pancreatic somatostatin inhibits the release of both insulin and glucagon and slows the activity of the insulin and glucagon and slows the activity of the digestive tract.digestive tract.

PP regulates secretion of pancreatic digestive PP regulates secretion of pancreatic digestive enzymes and inhibits release of bile by the enzymes and inhibits release of bile by the gallbladder.gallbladder.

Glucagon:Glucagon: Glucagon is a 29 amino acid polypeptide with extremely potent Glucagon is a 29 amino acid polypeptide with extremely potent

hyperglycemic properties. One molecule of this hormone can hyperglycemic properties. One molecule of this hormone can induce the release of 100 million molecules of glucose into the induce the release of 100 million molecules of glucose into the blood. blood.

The major target organ of glucagon is the liver, where it promotes:The major target organ of glucagon is the liver, where it promotes:

Breakdown of glycogen to glucose (glycogenolysis)Breakdown of glycogen to glucose (glycogenolysis) Synthesis of glucose from lactic acid and from noncarbohydrate Synthesis of glucose from lactic acid and from noncarbohydrate

molecules such as fatty acids and amino acids (referred to as molecules such as fatty acids and amino acids (referred to as gluconeogenesis).gluconeogenesis).

Release of glucose into the blood by the liverRelease of glucose into the blood by the liver

All these effects ↑ blood sugar levels.All these effects ↑ blood sugar levels.

Secretion of glucagon from the alpha cells is induced by, most Secretion of glucagon from the alpha cells is induced by, most importantly, low blood sugar levels but also by high amino acid levels importantly, low blood sugar levels but also by high amino acid levels in the blood (e.g. following a protein-rich meal). Rising blood sugar in the blood (e.g. following a protein-rich meal). Rising blood sugar concentration and somatostatin from the delta cells inhibit glucagon concentration and somatostatin from the delta cells inhibit glucagon release.release.

Insulin:Insulin: Insulin is a 51 amino acid protein consisting of two Insulin is a 51 amino acid protein consisting of two

polypeptide chains linked by disulfide bonds. It is polypeptide chains linked by disulfide bonds. It is synthesized as part of a larger molecule called proinsulin synthesized as part of a larger molecule called proinsulin and packed into secretory vesicles where its middle and packed into secretory vesicles where its middle portion is excised by enzymes to produce functional portion is excised by enzymes to produce functional hormone, just before insulin is released from the beta cell. hormone, just before insulin is released from the beta cell.

As mentioned earlier, insulin's main function is to lower As mentioned earlier, insulin's main function is to lower blood sugar levels but it also affects protein and fat blood sugar levels but it also affects protein and fat metabolism. metabolism.

In general, insulin:In general, insulin:

Increases membrane transport of glucose into body cells, Increases membrane transport of glucose into body cells, especially muscle and liver cellsespecially muscle and liver cells

Inhibits the breakdown of glycogen (it should not be confused Inhibits the breakdown of glycogen (it should not be confused with glucagon!) into glucose,with glucagon!) into glucose,

Increases the rate of ATP production from glucoseIncreases the rate of ATP production from glucose Increases the rate of glycogen synthesisIncreases the rate of glycogen synthesis Increases the rate of glucose conversion to fat.Increases the rate of glucose conversion to fat.

Insulin binds to tyrosine kinase receptors, but Insulin binds to tyrosine kinase receptors, but mechanism of action, including type(s) and mechanism of action, including type(s) and specific roles of second messengers, are poorly specific roles of second messengers, are poorly understood. understood.

The beta cells are stimulated to produce insulin The beta cells are stimulated to produce insulin primarily by elevated blood sugar levels, but also primarily by elevated blood sugar levels, but also by high blood levels of amino acids and fatty by high blood levels of amino acids and fatty acids. acids.

Several hormones also induce the release of Several hormones also induce the release of insulin, including glucagon, epinephrine, growth insulin, including glucagon, epinephrine, growth hormone, thyroid hormones, and glucocorticoids. hormone, thyroid hormones, and glucocorticoids.

In contrast, somatostatin inhibits insulin release.In contrast, somatostatin inhibits insulin release.