ANTERIOR AND POSTERIOR PITUITARY CELLS AND ITS FUNCTIONS

12/27/20151

ANTERIOR AND

POSTERIOR PITUITARY

CELLS & ITS

FUNCTIONS

DR. VIJAY JAISWAL, Asso. Professor ,

Fellow Pediatric . Endocrinology

The pituitary gland is the central regulator of growth,

reproduction,and homeostasis. MASTER GLAND ‘

PEEYUSH GRANTHEE’

It functions through hormone signaling pathways that

co-ordinate signals from the brain and the

hypothalamus to target organs, such as the adrenals,

thyroid, and gonads.

The pituitary lies within the sella turcica at the base of

the brain, and the mature gland consists of the

adenohypophysis (anterior and intermediate lobes)

and the neurohypophysis (posterior lobe).12/27/2015DR. VIJAY JAISWAL2

The posterior lobe consists of axons of neurons,

the cell bodies of which reside in the

hypothalamus.

The posterior pituitary stores and releases

oxytocin, which is required during parturition and

lactation, and arginine vasopressin (AVP), which

regulates water balance

12/27/2015DR. VIJAY JAISWAL3

The function of the pituitary gland is intricately linked

with that of the hypothalamus. Stimulatory and

inhibitory releasing hormones are secreted from the

hypothalamus, which regulate hypothalamo-pituitary–

target gland axes.

These include

• corticotrophin-releasing hormone (CRH)

•thyrotrophin-releasing hormone (TRH),

•GH-releasing hormone(GHRH)

•gonadotropin-releasing hormone (GnRH)

inhibitory hormones dopamine and somatostatin.

The hormones secreted by the posterior lobe are

synthesized in the magnocellular neurons of the

paraventricular and supraoptic nuclei that lie within

the hypothalamus12/27/2015DR. VIJAY JAISWAL4



12/27/2015DR. VIJAY JAISWAL

7


Hormonal deficits can be one part of a syndrome, with

patients manifesting abnormalities in extra pituitary

structures,

usually in structures sharing a common embryological

origin, such as the eye and forebrain.


BLOOD SUPPLY

OF PITUTARY

BLOOD SUPPLY

The hypothalamus is supplied by circle of Willis and

most venous return into vein of Galen.

Blood from supr. Hypophyseal artery, which arise

from internal carotid arteries , flow through capillary

plexus in the median eminence to enter in a

sinusoidal network in the pituitary stalk. Blood

passes from these sinusoids into a second capillary

network plexus in anterior pituitary. This venous

portal system linking these two capillary network is

called the Hypothalamo – pituitary portal system .

The infundibulum or pituitary stalk carries both

the portal blood supply and the neural tracts to the

pituitary gland, so damage to the pituitary stalk

results in anterior and posterior pituitary dysfunct12/27/2015DR. VIJAY JAISWAL11

Development of pituitary gland


1 Formation of the pituitary placode derived from

the ectoderm

at the roof of the primitive oral cavity, which makes

contact with the floor of the ventral diencephalon.

2 Invagination of the oral ectoderm and formation

of a rudimentary Rathke’s pouch with evagination of

the ventral diencephalon to form the posterior

pituitary.

3 Formation of the definitive Rathke’s pouch.

4 Spatial and temporal differentiation of the

various cell types within the mature anterior pituitary

gland.12/27/2015DR. VIJAY JAISWAL13

Early developmental genes and transcription

factors

A number of signaling molecules and transcription

factors

are implicated in early pituitary organogenesis and

lineage

differentiation.

They are expressed sequentially at critical periods of

pituitary development, and the expression of many is

subsequently attenuated


Morphogenetic signals (BMP, FGF, SHH, Wnt)

Close interaction between the oral and neural

ectoderm is required for initial pituitary development.

Extrinsic molecules within the ventral diencephalon

and the surrounding structures,such as

• bone morphogenetic proteins 2 and 4 (BMP 2,4)

• fibroblast growth factor 8 (FGF8),

•Sonic Hedgehog (SHH)

•Wingless (Wnt4),

•thyroid transcription factor (Ttf1; also called Nkx2.1),

play critical roles in early organogenesis.

Rathke’s pouch develops in a two-step process

requiring at least two sequential inductive signals from

the diencephalon.12/27/2015DR. VIJAY JAISWAL15



Hesx1

Homeobox gene Expressed in embryonic stem cells

Hesx1 is one of the earliest markers of the pituitary

primordium,suggesting that it has a critical role in

early determination and differentiation of the gland. It

is also called Rpx (Rathke’s pouch homeobox) and

is a member of the paired like class of homeobox

genes.


Isolated hormone abnormalities

GH1 Isolated growth hormone deficiency R, D

GHRHR Isolated growth hormone deficiency R

TSH beta Isolated TSH deficiency and secondary hypothyroidism

R

TRHR Isolated TSH deficiency and secondary hypothyroidism R

T-PIT ACTH deficiency R

PC 1 ACTH deficiency, hypoglycemia, impaired glucose tolerance,

HH, obesity R

POMC ACTH deficiency, obesity, red hair R

DAX1 Adrenal hypoplasia congenital and HH XL

GnRHR Isolated gonadotropin deficiency and HH R

KAL-1 Kallman syndrome XL

FSH beta Primary amenorrhea; defective spermatogenesis R

LH beta Delayed puberty R

AVP Diabetes insipidus R


Combined pituitary hormone deficiency (CPHD)

PIT1 GH, TSH, prolactin deficiencies R, D

PROP1 GH, TSH, LH, FSH, prolactin, evolving

ACTH deficiency R

Specific syndrome

HESX1 Septo-optic dysplasia R, D

LHX3 CPHD (GH, TSH, LH, FSH, prolactin), short

neck, limited rotation R

LHX4 CPHD (GH, TSH, ACTH) with cerebellar

abnormalities D

SOX3 IGHD and mental retardation XL

GLI2 Holoprosencephaly and multiple midline

defects D

GLI3 Pallister–Hall syndrome D

Pitx2 Rieger syndrome12/27/2015DR. VIJAY JAISWAL20

Prop1 is a pituitary-specific paired-like homeodomain

activator. Both transcription factors are believed to bind

to the same DNA response elements.

Hesx1 and Prop1 function as opposing transcription

factors

and that the careful temporal regulation of their

expression

is critical for normal pituitary development

Premature expression of Prop1 can block pituitary

organogenesis. Prolonged expression of Hesx1 with the

obligate co-repressor TLE1 can block Prop1-dependent

activation, which normally results in the appearance of

somatotrophs, lactotrophs, thyrotrophs, and

gonadotrophs.

switch between binding of a paired homeodomain

repressor Hesx1 for a paired homeodomain activator


Pitx1 and Pitx2

Pitx1 and Pitx2 are paired-like homeobox genes

expressed in the fetal pituitary and in most cells of

the adult gland. They play an important role in the

development of Rathke’s pouch and anterior

pituitary gland.

Pitx2 is first expressed in the embryo in oral

epithelium and oral ectoderm. Pitx2 is expressed

in the developing Rathke’s pouch in addition to

the mesenchyme near the optic eminence, the

basal plate of the central nervous system (CNS),

the forelimbs, and domains of the abdominal

cavity. It appears to be required for pituitary

development shortly after formation of the

committed pouch.


Lhx3 and Lhx4

Lhx3 and Lhx4 belong to the LIM family of homeobox

genes

that are expressed early in Rathke’s pouch. At least

three different

isoforms of Lhx3 have been described in mammals,

each with distinct expression patterns and

transcriptional properties

Maintenance of Lhx3 persists in the adult pituitary,

suggesting a maintenance function for one or more of

the anterior pituitary cell type

Lhx4 is a closely related gene expressed in specific

fields of the brain and spinal cord.

Like Lhx3, Lhx4 is expressed throughout the

invaginating pouch . Subsequent expression at is

restricted to the future anterior lobe.12/27/2015DR. VIJAY JAISWAL23


Lhx3 activates the αGSU (Glycoprotein sub Unit

)promoter and, together with Pit1, acts synergistically to

activate TSH-β and prolactin promoters and the Pit-1

enhancer.

Lhx3 is one of the earliest markers for cells

destined to form the anterior and intermediate lobes,

and continued expression is essential for the formation

of gonadotrophs, thyrotrophs, somatotrophs, and

lactotrophsTerminal cell differentiation

Terminal pituitary cell differentiation is a culmination of

the interaction between extrinsic signaling molecules,

such as FGF8, BMP2, BMP4, BMP7, and Wnt5A, and

transcription factors, such as Lhx3, Lhx4, GATA2, Isl1,

Prop1, and Pit1


Prop1

Prop1 (Prophet of Pit1) is a pituitary-specific

paired-like

homeodomain transcription factor, first expressed

in the

dorsal portion of Rathke pouch,

It is believed to be required for the expression of

Pit1, as there is a failure of determination of Pit-1

lineages, lack of Pit-1 gene activation, and

absence of progression to mature cells which

harbors a homozygous missense mutation (S83P)

in the Prop1 gene.

The size of the pituitary gland is considerably

reduced less than 1% of the normal complement

of somatotrophs, markedly reduced numbers of

lactotrophs and thyrotrophs, and reduced

expression of gonadotropins .

Pit1

Pit1 (now called POU1F1) is a pituitary-specific

transcription

factor belonging to the POU homeodomain family. It has

also

been called GH factor 1 (GHF1), because it was first

identified

as a regulator of GH1 transcription.

Apart from GH1, Pit1 binding sites have been identified

in the promoters of the prolactin and TSH-β genes. Pit1

is expressed relatively late during pituitary development

and expression persists throughout life.

Pit1 is sufficient to activate the minimal elements in

the GH1 promoter necessary for cell-specific

expression, it requires other factors, such as Zn-15, a

zinc finger transcription factor, for synergistic

activation of the GH1 gene.Pit1 is essential for the

development of somatotrophs, lactotrophs, and

thyrotrophs in the anterior pituitary. 12/27/2015DR. VIJAY JAISWAL26

Anterior pituitary hormones and their

deficiencies

Growth hormone

Somatotrop account for 40–50% of anterior pituitary

gland. The human GH gene (GH-N or GH1) forms part

of a cluster of five homologous genes [GH1, hCS-

L(CSHP1), hCS-A (CSH1), hGH-V (GH2), hCS-B

(CSH2)] located on the long arm of chromosome 17

(17q22–24),The full-length transcript from the GH-N gene encodes a

191-amino-acid 22 kDa protein that contains two

disulfide bridges and accounts for 85–90% of

circulating GH.

Within both the proximal promoter and the LCR are

located

binding sites for the pituitary-specific transcription factor

Pit1


•The half-life of hGH is less than 20 min. It binds to

the

GH receptor (GHR), which is present in a number of

tissues.

•The hormone sequentially dimerizes its receptor,

activating

a receptor-associated tyrosine kinase JAK2 that in

turn is

autophosphorylated and also phosphorylates the

GHR. This

leads to signal transduction using the mitogen-

activated

protein kinase (MAPK), signal transducer and

activator of

transcription (STAT) and phosphatidylinositol (PI) 3-

kinase

These include early response genes encoding

transcription factors (c-jun, c-fos, and c-myc implicated

in cell growth, proliferation, and differentiation) and

insulin-like growth factor I (IGF-I), which mediates the

growth-promoting effects of GH


Actions

GH is secreted in a pulsatile fashion. Peak

concentrations are achieved during sleep, but

secretion is also increased during emotional stress,

exercise, hypoglycemia, protein meals, and prolonged

fasting. Pharmacological agents used to increase hGH

secretion include insulin, glucagon, clonidine, L-dopa,

and propranolol.

Apart from its actions on linear growth, GH is anabolic,

lipolytic, and diabetogenic. It increases calcium

absorption and is believed to improve bone density.

Administration of hGH results in a reduction in body fat

and

an increase in muscle mass .12/27/2015DR. VIJAY JAISWAL29

GH acts indirectly on bone growth by stimulating the

synthesis of IGF-1, the main GH-dependent growth

factor. IGF-1 Is a single-chain polypeptide containing

70 amino acids. It shares considerable homology with

insulinIt is synthesized in the liver and circulates bound to

several binding glycoproteins.

The principal binding protein is IGFBP-3, the

secretion of which is also regulated by GH.

Measurement of IGF-1 correlates well with spontaneous

GH secretion and is used in the diagnosis of GH

deficiency, but its concentration is altered in a number of

other disease states, such as hypothyroidism,

malnutrition, poorly controlled diabetes, and chronic

disease12/27/2015DR. VIJAY JAISWAL30

Regulation

The secretion of GH is pulsatile with a predominant

nocturnal

component. Pulsatility is regulated by GH-releasing

hormone

(GHRH), a 44-amino-acid protein that stimulates GH

secretion, and somatostatin, an inhibitory hormone

containing 14 amino acids. The secretion of these

hypothalamic hormones is influenced by

neurotransmitters and neuropeptides, such as

dopamine, catecholamines, histamine, serotonin,

gamma aminobutyric acid (GABA), and opiates.

GH and growth factors such as IGF-I and IGF-II exert

negative feedback on the hypothalamic regulators of GH

secretion, whereas sex steroids such as testosterone

and estrogen increase hGH secretion.


Thyrotrophin or thyroid-stimulating hormone

Thyrotrophin is a glycoprotein consisting of two non

covalently bound chains of amino acids (α and β) that is

synthesized and stored within the thyrotrophs of the

pituitary gland.

The α-chain consists of 92 amino acids and shares

homology with other pituitary glycoproteins FSH and

LH.The β-chain contains 110 amino acids and is TSH

specific

Actions

The primary function of TSH is to stimulate the thyroid

gland

to secrete triiodothyronine (T3) and thyroxine (T4 ). Its

actions include stimulation of the iodide pump on the cell

membrane transporting iodide into the cell, stimulation of

the synthesis of the thyroidal storage protein

thyroglobulin, and stimulation and synthesis of T4 and


TSH binds to its cell membrane receptor, which

consists of seven transmembrane domains, four

intracellular domains, and a long extracellular

sequence with six potential glycosylation sites. It is

a G-protein-coupled receptor that stimulates adenyl

cyclase activity, activation of protein kinase A, and

subsequent phosphorylation.


Regulation

TSH secretion is pulsatile with peak

concentrations at night. Its secretion is stimulated

by hypothalamic TRH acting via its Gprotein coupled

receptor and inhibited by somatostatin and

dopamine.

The thyroid hormones negatively feedback both at

the

pituitary level on TSH secretion and at the

hypothalamic level on TRH. Other factors impinging

on TSH secretion include estrogen which increases

the number of TRH receptors on the thyrotropes

decrease in the ambient temperature acting as a

potent stimulator of TSH.12/27/2015DR. VIJAY JAISWAL34

Adrenocorticotropic hormone

ACTH is a 39 amino acid polypeptide with a short

biological

half-life of approximately 8 min. It is synthesized and

stored

within the corticotropes of the anterior pituitary that

account for about 10% of the adenohypophysis.

Actions and regulation

Actions

The primary function of ACTH is to stimulate the zona

fasciculata

and zona reticularis of the adrenal glands to produce

glucocorticoids (mainly cortisol) and adrenal

androgens.

Like other peptide hormones, ACTH binds to its specifi c

membrane receptor on the adrenocortical cells to

increase the formation of cyclic AMP and activation of

various protein kinases



Regulation

The secretion of ACTH follows a circadian rhythm with

peak

concentrations in the early hours of the morning and

low concentrations in the late evening.

As a result, cortisol secretion is circadian with peak

concentrations at around 0800 hours and a nadir

at midnight.

This rhythm can be disrupted by shifts in day–night

patterns.

Gonadotropins

The reproductive system is unique because of changes

in the secretion

of reproductive hormones taking place throughout life.

The

gonadotropins, FSH and LH, are glycoproteins

composed of two

subunits: α and β. The α-subunit is identical to the α-

subunit of

TSH (gene encoding the α-subunit is located on

chromosome

6q12-q21) and the specific biological activity of both

hormones resides in the β-subunit.

LH secretion is pulsatile in both sexes but sexual

dimorphism in

physiological secretory patterns becomes evident with

maturity of

the hypothalamo-pituitary-gonadal axis. An increased

nocturnal

LH release is the first sign of the onset of puberty.

.




Actions

Both hormones bind to membrane receptors in their

ovarian and

testicular cells, activate the G-protein coupled complex

and stimulate adenyl cyclase.

FSH regulates gametogenesis in males and females

while LH is thought to be primarily responsible for

gonadal steroid secretion

Regulation

Pulsatile release of hypothalamic GnRH regulates the

secretion of the pituitary hormones LH and FSH which

stimulate the testis

and ovary at puberty to increase the gonadal steroid

secretion and develop secondary sexual characteristics.

There is a surge in gonadotropin and gonadal steroid

secretion in the neonatal period with concentrations

similar to those reached during puberty following the first

few months of life, the gonadotropin axis

remains quiescent until puberty, when concentrations

rise again.

GnRH-synthesizing neuronal migration, from their first

appearance

in the embryonic medial olfactory placode to their final

position in the medio basal hypothalamus, is complete

by around


Estradiol and progesterone act via both the pituitary

and hypothalamus to have a negative effect on

gonadotropin

secretion.

However, if plasma estradiol concentrations are very

high for a period greater than approximately 36 h in

the absence of plasma progesterone, a positive

feedback influence is exerted with an LH surge as

seen in the mid-menstrual cycle in females.

FSH secretion is also regulated by inhibin, a protein

molecule secreted by the follicular granulosa cells in

the female and Sertoli cells in the male.


Prolactin

Action, regulation and deficiency

Prolactin is a 199 amino acid protein with its gene

located on

chromosome 6p22.2-21.3.

The principal functions of prolactin are growth and

development of the breasts and initiation and

maintenance of lactation in postpartum women.

It also has some role in regulation of gonadal function

by stimulating the generation of LH receptors in the

gonads in both sexes.

The mechanism of action of prolactin is similar to

other protein molecules by stimulating the tyrosine

kinase pathway and subsequent intracellular protein

phosphorylation.



The release of prolactin is under the control of the

hypothalamus with afferent impulses from sensory

receptors, primarily around the nipples.

The dominant hypothalamic influence is

inhibitory and the principal inhibitory hormone is

dopamine.

Other molecules exerting an inhibitory role are

norepinephrine, histamine and serotonin acting at

either a hypothalamic or pituitary level.

TRH, in addition to stimulating the release of TSH,

is also the principal prolactin stimulatory hormone.

Thyroxine and estrogen can modulate the number

of TRH receptors in the lactotropes, thereby

influencing prolactin release

Posterior pituitary hormones

The neurohypophysis consists of the supraoptic and

paraventricular hypothalamic nuclei containing the

cell bodies of the magnocellular neurosecretory

neurons that secrete vasopressin and oxytocin, the

supraoptico-hypophyseal tract that includes the

axons of these neurons, and the posterior pituitary

where the axons terminate on capillaries of the

inferior hypophyseal artery.

Arginine vasopressin

Vasopressin is a basic nano peptide with a disulfide

bridge between

the cysteine residues at positions 1 and 6. Most

mammals have

the amino acid arginine at position 8. 12/27/2015DR. VIJAY JAISWAL43


The preprohormone is synthesized in the magnocellular

neuron cell body, following which the signal peptide is

cleaved.

Stimulation of vasopressinergic neurons results in the

opening of voltage gated Calcium channels in the nerve

terminals, which through

transient calcium influx results in fusion of the neuro

secretory

granules with the nerve terminal membrane and release

of their

contents into the circulation.

The half-life of vasopressin is short, approximately 5–15

min.


Vasopressin acts via three G-protein coupled

receptors:

• pressor effects via V1 receptors,

• renal effects via V2 receptors (V2-R)

• action on corticotropes to secrete ACTH in synergy

with CRH via V3 receptors. Activation of the V2-Rleads to a biphasic increase in the expression of the

water channel

protein aquaporin 2. This then allows reabsorption of

water from

the duct lumen along an osmotic gradient, with excretion

of

concentrated urine.

The main regulatory factors in determining vasopressin

secretion

are osmotic status, blood pressure and circulating


Oxytocin

The oxytocin gene lies on chromosome 20p13 and

consists of

three exons, which, like vasopressin, encodes a

polypeptide precursor with an amino-terminal signal

peptide, the oxytocin

peptide, neurophysin and a carboxy-terminal peptide.

The half-life of oxytocin is short. Oxytocin binds to a G-

protein coupled cell surface receptor on target cells to

mediate a variety of physiological effects largely

concerned with reproductive function, namely the

regulation of lactation, parturition and reproductive

behavior.

In humans, women lacking posterior pituitary function

can breast-feed normally, illustrating that oxytocin not



•Pituitary gland is the central regulator of growth ,

Reproduction and homeostasis.

•Anterior Pituitary Consist of 5 cell types

and 6 hormones.

Somatotrop constitute major bulk of Anterior

Pituitary (40-50%)

•Anterior Pituitary develops from oral ectoderm while

Posterior develop from neural ectoderm.

•Any damage to Pituitary stalk can result Anterior and

Posterior Pitutary dysfunction


•Clinical Features of Hypopituitarism are

Variable both in Severity

and Number of hormone Deficiencies

•Complete Evaluation of H-P Axis is indicated

in any patient suspected of having one hormonal

Deficiency

•HesX1 is one of the earliest markers of early

determination & differentiation of the pituitary gland.

•Cascade of signaling molecules and transcription

factors have crucial role in organ commitment, cell

proliferation and terminal differentiation and the final

product is culmination of this coordinated process

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ANTERIOR AND POSTERIOR PITUITARY CELLS AND ITS FUNCTIONS

Health & Medicine