Hypothalamus and Anterior Pituitary - Rutgers Universityadvis/800_endo_summer_PDFs/800_04... · Hypothalamus and Anterior Pituitary 04 • The “story line” concept: introduction

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Hypothalamus and Anterior Pituitary

04

• The “story line” concept: introduction to communication, “reflex arc” model, neuroendocrinology, hierarchies, integration

• The “hypothalamic - pituitary” unit: neurovascular hypothesis, hypothalamic and hypophysiotropic neurohormones to anterior pituitary.

• The “neuroendocrine control”, “hierarchies” and “integration” sites: the ME as neuroendocrine integration site, other neuroendocrine integration sites

• The “anterior pituitary”: embriological origin, amplification unit for hypophysiotropic hypothalamic signals

• Regulators of anterior pituitary secretion: regulators of ACTH and of GH secretions and their mechanisms of action

• Neurohormones (GnRH, TRH, GHRH, SS, CRH, DA): a list of hypophysiotropic neurohormones and their effects

The “Story Line” Concept

I suggest you put this information into a table YOU design !!!

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S E

sensor

integrator

center

effector

afferent

“story line” efferent

“story line”

negative feedback

“story line”

diagram for a control system

as that present in a refrigerator

a “reflex arc”

a base for a

control model

S

E … if story lines are linked through an integrator and

a negative feedback then you have “control”…


( )

( )1

( )3

S

E

S

E

( )2

e.g.

Insulin ( 1)

Glucagon ( 2) Cortisol ( 3)

Epinephrine

SS and GRH

GH

T3 - T4 others ...

S

E

Blood glucose as example of a multihormonal control


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The “Hypothalamic- Pituitary” Unit

• Hypothalamus

• Pituitary Stalk

• Anterior / Posterior Pit.

• Hypothalamic Nuclei

• Vascular link to AP

• Neuronal link to PP

• Stalk transection

• Kidney transplant

• Neonate pituitary

• Harris, Halaz, Yalow, Shally, Guilleman (NTC)

• Neuroendocrine control (pulsatile, circadian, episodic)

pulsatile

circadian

episodic

LH

A

CT

H

GH

S

E

TARGET

FINAL ENDOCRINE EFFECT

N T C

hypothalamus

long

loop

negative

feedback short and

ultrashort

negative

feedbacks

hierarchies:

gonadal adrenal

thyroid others

A P

The “Neuroendocrine Control”, “Hierarchies” and “Integrators”

• variable under control (t°C / °F)

• thermostat (set point)

• t°C / °F detector (feedback)

• Integrator ( )

• common language

• error signal (on/off)

• engine (amplifier)

NTC =

neuroendocrine

transducer

cells

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S

E

C S

Integrator ( )

Error signal (NTC)

AP

gland

controlled hormone

feedback

detector

negative

feedback loop


• variable under control (t°C / °F)

• thermostat (set point)

• t°C / °F detector (feedback)

• Integrator ( )

• common language

• error signal (on/off)

• engine (amplifier)

E2

P4 receptor

C S

CRH

AP

adrenal

cortisol

Cortisol.

receptor

C S

TRH

AP

thyroid

T3 / T4

T3

receptor

C S

GnRH

AP

gonad

E2 / P4

N TC

gonadal

hierarchy adrenal

hierarchy

thyroid

hierarchy

S

E


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ARN-ME and PVN, two hypothalamic integration center

S

E ARN-ME PVN



S

E

ME

PVN

POA

The PVN has outputs:

to ARN-ME area to posterior pituitary

to midbrain (ANS)

GnRH

TRH, GHRH

SRIF / SS DA, CRH, VIP


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S

E


ARN-ME

AP

PVN

PP ANS

What are integrators for, and from where do their inputs

came from, and where do their outputs go to ??


S

E





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S

E





The “Anterior Pituitary”

AP function and “story lines”

Anterior Pituitary Hormones

TSH

FSH

LH

GH

PRL

ACTH

POMC

Hormone Target Major Action

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• Embriological origin

• Anatomical / functional links to the brain

• Hypophysio-tropic neuro-hormones

• Hormone RIAs

anterior pituitary

roof of the mouth

Rathk’es pouch adenohypophysis

vascular link

posterior pituitary

hypothalamic projection

axonal transport neurohypophysis

neuronal link

The pituitary gland is located in a depression of

the basiesphenoid bone called the “sella turcica”





• Hormone RIAs

Lesion 1


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• Hormone RIAs


this

lecture

next

lecture

(vascular link)

(neuronal link)

Hypophysiotropic Hormones




• Hormone RIAs


CRH

GnRH

GHRH

Ghrelin

SS

5HT

DA

TRH

AVP

Hypophysiotropic Hormones Hormone

Aminoacids Hypothalamic

Source Pituitary Action

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• Hormone RIAs


Hypophysiotropic Hormones

TRH

GnRH

SS

CRH

GHRH

Grhelin

VP




• Hormone RIAs


How to measure Hormones

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• Regulators of ACTH secretion

• Regulators of GH secretion

Regulators of AP secretion

S

E

The

hypothalamic – pituitary –

adrenal hierarchy




S

E ACTH --->

Regulation of ACTH secretion

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S

E

POMC and

biosynthesis of ACTH

Feedback associated

with control of ACTH

(Addisson’s disease ???)




S

E

C S

CRH

AP

adrenal

cortisol

Cortisol.

receptor

adrenal

hierarchy

What does this

profile suggest

about the control of ACTH ???

Basal

release of ACTH

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S

E

(more

Info in

gluco-corticoid

lectures)




S

E

Mechanism of action

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S

E (more info on steroids, gluco and mineralocorticoids lectures)





S

E

the

growth hierarchy

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S

E

Regulation of GH secretion





S

E

(-Fb)

(this

lecture)

(lecture

on growth)

(last lecture)

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S

E What does this experimental profile suggests ?

GH

basal release

day

vs night




S

E

More on

growth and

metabolic

actions

of hormones

in later

lectures on

metabilism of:

a) water

b) glucose

c) mineral

d) growth

GH endocrine effects are also the reason why it

is abused as drug to enhance sport performance.

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S

E

More on

growth and

metabolic

actions

of hormones

in later

lectures on

metabilism of:

a) water

b) glucose

c) mineral

d) growth

GH endocrine effects are also the reason why it

is abused as drug to enhance sport performance.

wo

rklo

ad

fo

rce

GH and exercise performance

time in months



S

E

(+)

(-)

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S

E

Mechanism of action




1.6 meters

2.3 meters

(7’ 6”)

GH hyper-

secretion before and

after the closure of

epiphyseal

growth plate at puberty

Gigantism

S

E

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Acromegaly

S

E




Acromegaly S

E

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• anatomy, embryology, and hierarchies (gonadal, thyroid, GH, adrenal, Prl, intermedin).

• GnRH: structure, gene expression, receptor, secretion, action, Kallman syndrome, clinical use.

• TRH: structure, receptor, secreting cells, regulation, actions, clinical use.

• GHRH: structure, receptor, secretion, patophysiology, clinical use.

• SRIF: structure, receptor, secretion, analogs.

• CRH: structure, receptors, regulation, secretion and patophysiology, clinical use.

• DA: synthesis and DA neurons, regulation of Prl, receptors, hyperprolactinemia and D2R agonists.

• gases as neural messengers (neurohormones).

Hypophysiotropic neurohormones

GnRH

LHRH

LH / FSH

P4, T, E2

TRH

TSH

T3, T4

GRH

SS

GH

IGFs

CRH

ACTH

cortisol

DA

VIP

Prl

MSH - RF

5HT

MSH

• decapeptide derived from a 92 aa precursor encoded by one gene which also encodes GAP

• its receptor has 7- transmembrane domains, characteristic of G protein - linked receptors. Its AP content changes with physiological states. Constant GnRH infusion downregulates the GnRH- receptor

• GnRH regulates LH / FSH synthesis and release by a Ca - dependent mechanism involving phosphoinosi-tide hydrolysis, PKC activation, and calmodulin

• Kallman syndrome, precocious puberty, hpg mouse

• sexual behavior, prostate cancer, endometriosis

GnRH

• is a tripeptide amide synthesized as part of a large prohormone termed prepro-TRH which contains 6 TRH copies encoded by one gene

• its receptor has 7- transmembrane domains, characteristic of G protein - linked receptors

• TRH actions are mediated by the phosphoinositol / Ca system (IP3, DAG, calmodulin, PKC)

• distribution of TRH receptors in brain suggest TRH is also a neurotransmitter / neuromodulator

• TRH appears to function as neurotrophic factor

• used in stimulation tests prior to new TSH assays

TRH

• 44 aa in more than a isoform coded in a large prohormone. Hypothalamic gene expression is under the control of GH, is sexually dimorphic and regulated by gonadal steroids (up by DHT)

• its receptor has 7- transmembrane domains, characteristic of G protein - linked receptors

• several second messenger systems mediate effects of GHRH: AC/cAMP, PLC/IP2, PLA/PGE

• GHRH neurons have SS receptors, GH pulses

• half of human GH - secreting tumors have point mutations of Gs gene that interferes with intrinsic GTPase activity and lead to constitutive activation

GHRH

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• a tetradecapeptide whose gene sequence is well conserved in evolution. Post-translational processing of proSS by peptidases / convertases is also conserved and determine the SS tissue specificity

• its five receptor subtypes have 7- transmembrane domains, typical of G protein - linked receptors

• SS inhibits AC activity on binding to its receptor by stimulating Gi. Additional SS open K channels hy-perpolarizing the cell and decreasing Ca influx through voltage sensitive channels

• since many tumors expressed SS-receptors, SS agonists are used in their detection and treatment. SS antagonists are of potential use to increase GH

SS

• a 41 aa, synthesized as part of a prohormone which is processed enzymatically. The CRH gene is expressed widely. CRH-BP decreases its synaptic concentration and bioavailability

• its receptor has homology to the G - protein - coupled receptor superfamily, and has been linked to GC and to an increase in Ca by cAMP

• CRH is the primary hormonal regulator of the body’s stress response. It has a reciprocal positive interaction with AVP at the ME (?)

• CRH is used in stimulation tests, antagonists in depression, anorexia nervosa, anxiety, drug withdrawal. CRH-BP antagonists increase CRH

CRH

• is a catecholamine synthesized by hydroxylation of tyrosine and subsequent decarboxylation of L-Dopa

• D2 receptors regulate Prl. They have 7 transmem-brane domains, typical of G protein- linked receptors

• DA decreases cAMP (Gi) and ICF-Ca. Prl release is inhibited by low Ca and by Ca channel blockers

• hyperprolactinemia due to uncoupling of lactotrophs from hypothalamic DA.

• hyperprolactinemia causes hypo-gonadism, low libido & galactorrhea. It is treated by DA agonists. Prl response to haloperidol is a very good predictor of its antipsychotic effects

DA

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Hypothalamus and Anterior Pituitary - Rutgers Universityadvis/800_endo_summer_PDFs/800_04... · Hypothalamus and Anterior Pituitary 04 • The “story line” concept: introduction