HYPOTHALAMUS AND ITS HORMONES

HORMONES OF THE PITUITARY

Jana Jurcovicova

ANATOMICAL NOTES

Pituitary has a coordinating role in regulation of peripheral endocrine glands. It is connected with with part of diencephalon - hypothalamus to form

hypothalamo-pituitary complex.

Hypothalamus acts as a regulating and connecting center which enables the control of endocrine functions by central nervous system.

Hypothalamus is located on the base of third ventricle and extends between

- mammilary bodies (caudally) - optic chiasm (frontally) - optic tract (laterally) - thalamus (dorsally)

On its base is median eminence, an important structure where converge regulatory pathways form hypothalamus into peripheral blood.

BASAL VIEW OF THE HYPOTHALAMUS

HYPOTHALAMO-HYPOPHYSEAL CONNECTION

Central part of neuroendocrine regulation is hypothalamo-hypophyseal complex. Structural components of this complex are neurosecretory cells grouped into secretory nuclei located around the third ventricle. These secrete neuropeptides into portal blood connecting hypothalamus with adenopituitary. The other cell groups secrete neuropeptides to systemic circulation through posterior lobe via long axons of magnocellular hypothalamic neurons.

Pituitary is located in sella turcica and is composed from 2 distinct structures - adenopituitary and posterior pituitary

arcuate nucleus and other nuclei

supraoptic and paraventricular nuclei

adenopituitar hormones

posterior pituitary hormones

ENDOCRINE HYPOTHALAMUS

Hypothalamic secretory nuclei synthesize neuropeptides regulating adenopituitary secretion. These either exert either stimulatory or inhibitory effects.

There are 4 stimulatory - releasing hormones

and 2 inhibitory - statins

releasing hormones:

reproduction function activates gonadotropin releasing hormone - GnRH

growth hormone activates growth hormone releasing hormone - GHRH

thyroid function activates thyrotropin releasing hormone – TRH,

adrenocortical function activates corticotropin releasing hormone – CRH.

inhibiting hormones (statins)

growth hormone inhibits somatostatin - SRIF (mild inhibitory activity also on TSH)

prolactin inhibits prolactostatin - dopamine

TOPOGRAPHY OF ENDOCRINE HYPOTHALAMUS

The highest endocrine activity resides in medial hypothalamus (tuberal region), then lateral and proptic regions

Medial hypothalamus: arcuate nucleus (ARC) containis GHRH, somatostatin and PIH, paraventricular nucleus (PVN) contains CRH and TRH. Periventricular nucleus contains somatostatin.

Lateral hypotalamus: supraoptic nucleus (SON) contains neurohypophyseal hormons arginin-vasopressin (AVP or ADH) and oxytocin, suprachiasmatic jnucleus (SCN) which is a central pacemaker of daily rhythms

Preoptic region is rich in GnRH.

SCHEMATIC DRAWING OF HYPOTHALAMIC NUCLEI

AC: anterior commissure PO: preoptic nucleus SC: suprachiasmatic nucleus OC: optic chiasma TC: tuber cinereum AP: anterior pituitary IN: infundibulum: posterior pituitary ME: median eminence AH: anterior hypothalamic nucleus SO: supraoptic nucleus TH: thalamus PV: paraventricular nucleus (not to be confused with periventricular nucleus, which is not shown) DM: dorsomedial nucleus VM: ventromedial nucleus AR: arcuate nucleus (associated with periventricular nucleus, which is not shown) LT: lateral nucleus PN: posterior nucleus MB: mamillary body

SCHEMATIC CROSS SECTION OF

HYPOTHALAMUS

Guyton and Hall, 2006

suprachiasmatic

Ganong and Hall, 2006

CROSS-SECTION OF THE ROSTRO - MEDIAL PART OF THE BRAIN

CROSS- SECTION OF THE MIDDLE PART OF THE BRAIN

HISTOCHEMICAL STAINING OF HYPOTHALAMIC NUCLEI

SECRETED HORMONE abbr PRODUCED BY EFFECT

Thyrotrophic-releasing hormone

(Prolactin-releasing hormone)

TRH, PRH

Parvocellular neurosecretory neurons

Stimulate thyroid-stimulating hormone (TSH) release from anterior pituitary (primarily)Stimulate prolactin release from anterior pituitary

Dopamine(Prolactin-inhibiting

hormone)

DA or PIH

Dopamine neurons of the arcuate nucleus

Inhibit prolactin release from anterior pituitary

Growth hormone-releasing hormone

GHRH

Neuroendocrine neurons of the Arcuate nucleus

Stimulate Growth hormone (GH) release from anterior pituitary

Somatostatin(growth hormone-inhibiting

hormone)

SS, GHIH, or SRIF

Neuroendocrine cells of the Periventricular nucleus

Inhibit Growth hormone (GH) release from anterior pituitaryInhibit thyroid-stimulating hormone (TSH) release from anterior pituitary

Gonadotropin-releasing hormone

GnRH or LHRH

Neuroendocrine cells of the Preoptic area

Stimulate follicle-stimulating hormone (FSH) release from anterior pituitaryStimulate luteinizing hormone (LH) release from anterior pituitary

Corticotropin-releasing hormone

CRH Parvocellular neurosecretory neurons

Stimulate adrenocorticotropic hormone (ACTH) release from anterior pituitary

OxytocinMagnocellular neurosecretory cells

Uterine contractionLactation (letdown reflex)

Vasopressin(antidiuretic hormone)

ADH or AVP

Magnocellular neurosecretory neurons

Increase in the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine

HYPOTHALAMIC HORMONES

HYPOTHALAMO – PITUITARY CONNECTION

Neurons of medial and preoptic hypothalamus end in the external layer of median eminence. Here they secrete neurohormones into primary plexus of portal vein system which converges along the pituitary stalk into the long veins. The neurohormones are then transported to adenopituitary secretory cells by veins of secondary blood plexus.

The existence of releasing / inhibiting hormone dates back to early 70-ties of the last century, when in was first proved that adenipotuitary is regulated by humoral factors coming from the hypothalamus. Many neurohormones are produced also in GIT and are released into circulation. Therefore the concentration of releasing hormones in portal blood must be higher than in peripheral blood system.

HYPOTHALAMO – PITUITARY CONNECTION

HYPOTHALAMO-PITUITARY REGULATION

pars tuberalis pars distalis

pars intermedia

pars nervosa

DEVELOPMENT AND STRUCTURE OF PITUITARY

posterioranterior

diencephalon

Rathke’s pouchof pharynx

neural tissueectoderm

Primary capilaryplexus

Neural lobe

AdenopituitaryAnterior lobe

OxytocinVasopresin

ACTH, GH,TSH, LH, FSH, Prolactin

Secretorycells

Chiasmaopticum

Nc. supraopticus

Nc. paraventricularis

Portal vein

***magnocellular

parvocellular

Hypothalamic neuronssecreting releasing, inhibitinghormones (nuclei:nARC, mPOA NPE)

HYPOTHALAMO - PITUITARY SYSTEM

INNERVATION OF ANTERIOR AND POSTERIOR PITUITARY BY NEURONES OF

PARAVENTRICULAR AND SUPRAOPTIC NUCLEI

STRUCTURES OF ARGININE VASOPRESSIN AND OXYTOCIN

LIST OF PITUITARY HORMONES

STRUCTURE OF PROOPIOMELANOCORTIN

PC1 – PROHORMONE CONVERTASE1

PC2 – PROHORMONE CONVERTASE2

REGULALION OF ENDOCRINE HYPOTHALAMUS

Feedback regulations

Neural inputs - mainly from higher CNS centers

Inputs from peripheral blood - leptin, ghrelin, insulin, cytokines , adenopituitary hormones, plasma levels of glucose, osmolality, steroid hormones (gonadal steroids and corticosteroids)

Light - photoperiod for the synchronization of circadian rhythms Stress – various stress stimuli depending on the character of stressor

FEEDBACK REGULATIONS

REGULATION OF HYPOTHALAMIC HORMONES BY SHORT LOOP AND

ULTRASHORT LOOP FEEDBACK

REGULATION OF HYPOTHALAMIC HORMONES BY COMPLEX FEEDBACK

SDDDDDDDDDDD

NEURAL STIMULI OF THE HYPOTHALAMUS

axon

vesicles with mediator

nucleus

dendrites

synaptic buttons

mitochondrion

postsynaptcireceptots

exocytosis

synapse

oligodendroglia

myelinRanviercleft

NEURON

NEUROTRANSMITTER SYSTEMS REGULATING HYPOTHALAMIC SECRETION

v

DOPAMINE SEROTONIN

NORADRENALINE

nigrostriatal pathway

mesocortical pathway

tuberoinfundibular pathway

NEUROTRANSMITTES REGULATING INDIVIDUAL RELEASING HORMONES

Although many findings come from animal studies and cannot be applied to human physiology absolutely, the principal regulatory mechanisms are equal. It is generally accepted that central noradrenaline plays a pivotal role in stimulation of GHRH, CRH, AVP a TRH. The effect of noradrenaline on GnRH is unequivocal. Central serotonin stimulates the secretion of GHRH and also pituitary prolactin via its not yet known releasing hormone. Central dopamine participates in the inhibition of GnRH and in stimulation of CRH. CRH is also stimulated by acetylcholine.

BLOOD BORNE STIMULI OF THE HYPOTHALAMUS

BLOOD BRAIN BARRIER (BBB)

Neurotransmitters and other molecules affecting neurosecretory activity of the hypothalamus (toxins, inflammatory agents) are found also in the circulation.Hypothalamus is protected from these influences by blood brain barrier (BBB). BBB is a complex mechanism regulating exchange of mediators between blood and CNS. It functions as protection from harmful stimuli (toxins) and also as transport system (for example glucose) into brain. BBB represented by tight junctions between endothelial capillary cells which are 100 times tighter than junctions in peripheral veins. These junctions are formed by ineractions of transmembrane proteins (claudins, occludins), adhesion molecules and cytoplasmic proteins (zona ocludens) bound to cytoskeletal actin filaments. BBB undergoes dynamic change during maturation, aging, under the influence of toxins or stress. For neuroendocrine secretion it is important that not all areas in brain are protected by BBB. These are: pineal gland, posterior pituitary, median eminence, and region around the third ventricle: area postrema, subcommissural organ, subfornical organ and organom vasculosum laminae terminalis

BRAIN ENDOTHELIAL CELL – CELL TIGHT JUNCTIONS

Engelhardt and Sorokin, 2009

transmembrane molecules

adhesion molecules

linked to actin skeleton

AREAS WITHOUT BLOOD BRAIN BARRIER

OVLT - organum vasculosum laminae terminalis; SFO – subfornical organ; ME – median eminence; SCO – subcomissural organ; PG – pineal gland; PL – posterior lobe; AP - area postrema;

MODULATION OF ADENOPITUITARY RESPONSIVENESS TO HYPOTHALAMIC

REGULATION

HYPOTHALAMIC REGULATION OF FOOD INTAKE

PHYSIOLOGY OF GROWTH HORMONE - GH

INCREASES PROTEIN SYNTHESES

DECREASES UTILIZATION OF CARBOHYDRATES IN MUSCLE STIMULATES OSTEOBLAST GROWTH AND IGF-I

HIGH LEVELS ARE DIABETOGENIC

STIMULATES IMMUNE SYSTEM

REGULATION OF GROWTH HORMONE (GH ) SECRETION

GROWTH HORMONE CHANGES DURING THE DAY

Guytom and Hall, 2006

NORMAL FUNCTIONS OF GH PRODUCED BY THE BODY

Main pathways in regulation of growth and etabolismEffects of growth hormone on the tissues is anabolic.Increased height during childhood is the most widely known effect of GH. Height is stimulated by at least two mechanisms:1.Through receptor mechanism GH directly stimulates division and multiplication of chondrocytes and osteoblasts.2.GH also stimulates the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. IGF-1 is generated within target tissues, thus it is an endocrine and paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.GH Increases calcium retention, and strengthens the mineralization of boneGH increases muscle mass through sarcomere hyperplasiaGH promotes lipolysis, release of FFA from fat tissue and enhanced production of acetyl-CoAGH inncreases protein synthesis by increased transport of aminoacids into cellsGH decreases glucose uptake in skeletal muscle and fat – hyperglycemic effectGH increases glucose production by the liverGH (in excess) promotes insulin resistanceGH stimulates the immune system

106

4

2

1

gigantism / acromegalytreatment - somatostatin

normal GH-deficit (treatment – GH administration)

IGF-1 [U/ml]

INSULIN-LIKE GROWTH F-1 (IGF-1) AND GROWTH

PHYSIOLOGY OF PROLACTIN - PRL

STIMULATES LACTATION (MILK PROTEIN CASEIN)

STIMULATES IMMUNE SYSTEM (DIRECT EFFECT ON IMMUNE CELL PROLIFERATION)

ANTIGONADAL ACTION (PROGESTERONE)

HORMONE LEVELS DURING PREGNANCY AND LACTATION

A- HCGB-ESTROGENSC-PRLD-PROGESTERONE

EFFECT OF BREST FEEDING ON PRL RELEASE

PRL levels in women after brest feeding on days 2, 4 ,6, post partumA- good lactation B- medium lactationC- poor lactation

F - before feedingG - after feeding

THE PINEAL GLAND

Known over 2000 years

Producing hormone of the night –MELATONIN

It aggregates pigment granules containing melanin, and thus makes

the skin lighter.

Pineal gland EPIPHYSIS has a shape of a pine cone

The pineal is consists of connective tissue , blood vessels, glial cells, and pinealocytes (which secrete melatonin).

Pinealocytes have larger, lighter staining nuclei

glial cells have small darker staining nuclei.

With age, calcified formations appear in the pineal gland (brain sand or corpora aranacea ).

HISTOLOGY OF PINEAL GLANDHISTOLOGY OF PINEAL GLAND

CIRCADIAN REGULATION OF MELATONIN PRODUCTION

EYE

Superior cervicale ganglion

LIGH EYE HINDBRAIN

SPINAL CORD

Synthesis ofN-acetyltransferases

ß-adrenergic receptors

α -adrenergic receptors

da

rk pe

riod

24-HOUR SECRETION OF MELATONIN IN HEALTHY AND ARTHRITIC RATS

MELATONIN

050

100

150200250

14 18 22 2 6 10

hour

pg

/ml

MAEN AC

MEAN cFA

** **

**

**+

+

CIRCADIAN SYNCHRONIZATION

CIRCADIAN OSCILATOR - SCN Principle of the circadian rhythmicity of the SCN are feedback mechanisms of clock genesSYNCHRONIZATION of the internal environment is the light/dark cycleSynhesis and release of melatonin is regulated from SCN, but synchronized by light/dark cycle. RHYTHM of melatonin secretion is indicator of CIRCADIAN PACEMAKER EFFECTS OF MELATONIN: improves quality of sleepactivates immune systemantioxidant (prevents oxidative stress)