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PROF.DR.ARZU SEVEN
 The hypotalamic hormones are released from the
hypothalamic nerve fiber endings around the
capillaries of the hypothalamic_hypophysial system in
the pituitary stalk and reach the anterior lobe of the
pituitary gland through the special portal system
 The hypothalamic releasing hormones are released in
a pulsatile manner
 The pituitary gland is a pea_sized oval organ encased
in a bone cavity of the skull (sella turcica) below the
brain
 The pituitary gland is divided into 2 lobes: the
posterior pituitary (neurohypophysis) is embryo
logically part of the brain and consists largely of
neurones which have cell bodies in the supraoptic and
paraventricular nuclei of the hypothalamus
 Hormones of the posterior pituitary are synthesızed
and packed in supraoptic and paraventricular nuclei of
the hypothalamus, transported along axons and stored
in the posterior pituitary before release in the
circulation
 The anterior lobe (adenohypophysis) accounts
approximately 80% of the gland, is embryologically
derived from ectoderm, has no direct anatomic
continuity with the brain
 Both posterior and anterior pituitary hormones are
controlled largely by the hpothalamus
 The hypothalamus functions as an integrative center
which orchestrates a large number of endocrine and
neural processes, and entrains them to relevant
external stimuli
 The endocrine systems that involve the hypothalamus,
pituitary and downstream organs are usually termed
“AXES” and are most usefully viewed as functional
units for the purposes of clinical diagnosis and
managemant
 AXES:
 1-hypothalamo_pituitary_thyroid axis
 2- hypothalamo_pituitary_adrenal axis
 3- hypothalamo_pituitary_gonadal axis
 4-the growth hormone axis
 5-the prolactin axis
 Growth hormone releasing hormone(GHRH)
 44_amino acid peptide synthesized as a part of a
108_amino acid prohormone in the arcuate and
ventromedial nuclei of hypothalamus and median
eminence
 GHRH + R --------adenyl cyclase
--------calcium-calmodulin system
GH secretion
 Negative feedback from GH and IGF-1
GHRH
SOMATOSTATİN
Growth hormone releasing
inhibiting hormone:
somatostatin(GHRIH)
 2 forms 14_amino acids
28_amino acids
 Produced from the same 116_amino acid gene product
 Somatostatin and its receptors are found throughout
the brain, and in other organs, notably gut
 Binding of somatostatin to its receptor is coupled to
adenyl cyclase by an inhibitory guanine nucleotidebinding protein- cAMP
 Somatostatin inhibits:
TSH
INSULIN
GLUCAGON
GASTRIN
Growth hormone(GH), prolactin and chorionic
somatotropin(CS: plasental lactogen) constitute
one hormone group
 They range in size from 190_199 amino acids
 Each has a single tryptophan residue
 Each has 2 homologous disulfide bonds
 Share common antigenic determinants
 All have growth promoting and lactogenic activity
GH
 Synthesized in somatotropes, a subclass of the
pituitary acidophilic cells
 Released in bursts with a periodicity of 3-4 hours and
greatest secretory activity occurs during sleep  no
meaningful referance interval
 Provocative tests / multipl samples over the course of a
day
 GH is essential for postnatal growth and for normal
carbohydrate, lipid and nitrogen metabolism:
 Transport of amino acids into muscle cells
growth)
Protein synthesis
RNA synthesis
DNA synthesis
like insulin
(during
 GH antogonizes the effects of insulin in carbohydrate
metabolism:
 Peripheral utilization of glucose + gluconeogenesis
hyperglycemia
 İnhibition of glycolysis in muscle
 Prolonged GH administration may result in diabetes
mellitus
 GH promotes the release of free fatty acids and
glycerol from adipose tissue,lipolysis (hormone
sensitive lipase activity )
 Oxidation of free fatty acids in liver
 Prolactin like effects such as stimulation of mammary
glands lactogenesis
 GH or more likely IGF-1 promotes (+) Ca,Mg and
phosphate balance and causes the retention of Na, K,
Cl (like IGF-1)
 During hypoglycemia GH stimulates lipolysis and
induces peripheral resistance to insulin
 The indirect growth-releated actions of GH are
mediated by IGF-1 :
 Promoting the proliferation of chondrocytes and the
synthesis of cartilage matrix in skeletal tissues:
stimulating linear growth
IGF-1 (insulin like growth factor 1):
 70 amino-acid single chain basic peptide
 Homology with proinsulin
 Acts like a paracrin hormone
 Liver is the major source of circulating IGF-1 whose
function is primarly feedback inhibition of GH
secretion
 In plasma and other extracellular fluids, IGF-1 is
complexed to IGF-1 bindings proteins (IGFBPs)
 IGF-1 works through the type 1 IGF receptor (similar to
insulin receptor) and linked to intracellular tyrosine
kinase activity
 Plasma reference interval for IGF-1 in adults aged 20-
60 years is fairly constant -a good marker of
integrated GH activity
 Lower in young children, rises dramatically during
period of growth and progression through puberty ,
falls after 6th. decade of life
IGF-2
 67 amino acids
 Has activity similar/ identical to multiplication
stimulating activity(MSA)
 Plasma levels are twice those of IGF-1
Clinical disorders of GH section
pathophysiology
 Basal IGF-1 or IGFBP-3 measurements may serve as a
preliminary screening test
 GH deficient dwarfs respond normally to endogenous
GH (regular injection of recombinant human GH)
Two types of target organ
resistance have been described :
 1-Laron type dwarfs
GH levels
IGF-1 levels
Lack of functional hepatic GH receptors
 2-Pygmies
 GH level normal
Post GH receptor defect
IGF-1 level
 Increased GH secreton later in life, after fusion of bony
epiphyses, causes ACROMEGALY
 The most likely cause is a pituitary adenoma
 Clinical features include:
 Coarse facial features
 Soft tissue thickening e.g. lips
 Spade-like hands
 Protruding jaw (prognathism)
 Sweating
 İmpared glucose tolarance or DM
 Diagnosis:
 An inadequate GH supression during standart 75
gr.oral glucose tolerance test and an elevated IGF-1
levels
 MRI evıdence of pituitary tumor
 Treatment:
 Surgery
 Long acting somatostatin analogues (octreotide )
 Pegvisomant (a GH antagonist)
 Radiation
Prolactin axis
 23KD a protein
 Homologous to GH
 Secreted by lactotropes ,acidophilic cells in the
anterior pituitary
 The number of these cells and their size increase
dramatically during pregnancy
 İt is under predominantly inhibitory control from the
hypothalamus
 Dopamine is an inhibitor of prolactin secretion
 TRH has prolactin-releasing properties
 The primary role ın humans occurs during pregnancy
when PRL binds to its receptor in mammary tissue
and stimulates the synthesis of milk proteins,
including lactalbumin
 PRL blocks FSH action on follicular estrogen secretion
and enhances progesterone levels by inhibiting steroid
metabolizing enzymes
 Hyperprolactinemia may result from:
 Prolactinoma (prolactin secreting pituitary tm)
 Deficient supply of dopamine from hypothalamus
 Use of antidopaminergic drugs
Symptoms
 Female: amenorrhea
galactorrhea
Male: impotance
prostatic hyperplasia
 Diagnosis:
 Pituitary imaging
 Dynamic test for prolactin secretion
 Treatment:
 Long-acting dopamine agonist drugs
 surgery
The hypothalamo-pituitary thyroid
axis
 TRH_manufactured in the hypothalamus and
transported to the anterior pituitary by the portal
circulation
 Modified tripeptide, synthesized in pulsatile fashion
 TRH stimulates TSH synthesis and secretion by
binding to G_protein coupled receptors on the
pituitary thyroptroph cell membrane, that are linked
to phospholipase C IP3 Ca release
preformed TSH secretion
 Chronic actions of TRH:
stimulation of TSH subunit biyosynthesis and TSH
glycosylation
 The number of TRH receptors are down regulated
bythyroid hormones and TRH
TSH(THYROTROPIN)
 Small glycoprotein, synthesized by pituitary
thyrotrophs
 α chain is identical to other glycoprotein hormones
(LH,FSH,β HCG)
 Specificity is conferned by the β-chain
 Pulsatil and circadian rhythm
 TSH, like TRH, acts via a specific G_protein coupled
receptoradenyl cyclasecAMP dependent protein
kinase
 TSH controls every aspect of thyroid hormone
biosynthesis and secretion :
 iodide transport
 İodothyronine formation
 Thyroglobulin proteolysis
 Thyroxine de_iodination
 TSH also stimulates growth of thyroid gland
 Negative feedback by thyroid hormones occurs at both
hypothalamic and pituitary levels
 At the pituitary level, T4 and T3 inhibit TSH secretion
(through regulation of gene transcription and TSH
glycosylation)
 T3 is a more potent feedback inhibitor than T4
 Much of feedback inhibition by T4 requires its
conversion to T3 by de_iodinase type2
THE HYPOTHALAMO-PITUITARYADRENAL AXIS
 Corcototropin releasing factor(CRF)
 41 amino acid peptide secreted by PVN
 Acts via G_protein coupled receptor
 cAMP second messenger system ; to stimulate both
synthesis and secretion of ACTH
 Vasopressin(VP) potentiates the response of the
pituitary to CRH
 Negative feedback by cortisol inhibits both CRH and
VP secretion
Adrenocorticotropic horomone
(ACTH)
 Synthesized as a 241_amino acid precursor
molecule,pro_opiomelanocortin (POMC)
 POMC is cleaved at multiple sites to release
hormonally active peptides,endorphins and MSH
 POMC may be produced in large quantities by certain
malignancies , giving rise to ectopic ACTH syndrome
 ACTH is composed of 39_amino acids with biologic
activity in the N_terminal 24 residues
 Secreted in stress-releated bursts, diurnal rhythm with
a peak at 05.00 h.
 Transported unbound in plasma, half life~ 10min.
 ACTH stimulates the synthesis and release of
glucocorticoid hormones by enhancing the conversion
of cholestrol to pregnenolone
 ACTH increases adrenal cortical growth (the trophic
effect) by enhancing protein and RNA synthesis.
 Negative feedback by cortisol occurs at both the
hypothalamic and pituitary levels:
Fast feedback alters the release of CRH and
CRH_mediated ACTH secretion, slow feedback results
from reduced synthesis of CRH plus supression of
POMC gene transcription, which results in reduced
ACTH sytnhesis
THE HYPOTHALAMO-PITUITARYGONADAL AXIS
 Gonadotropin releasing hormone(GnRH)
 Decapeptide synthesized by various hypothalamic
nuclei and transported to the pituitary by portal
system
 Secreted in a pulsatile fashion
 Induces the synthesis and secretion of both FSH and
LH
 Has a major role in the gonadal funcion in both males
and females
 Its release is subject to negative feedback by
progesterone, prolactin and sometimes estrogen
 GnRH mechanism :
 Ca (intracellular)
 Hydrolyes phospho inositides
 Activates protein kinase C
 Long acting GnRH agonists can cause downregulation
of GnRH receptors and reduced FSH and LH secretion
( to treat prostate cancer, to prepare infertile women for
assisted_conception programs)
GONADOTROPHINS (FSH,LH,β HCG)
 FSH and LH are glycoproteins with an identical
α_subunit (also shared with TSH ) and a specific
β_subunit
Follicular cells(ovary)
growth of graff follicule
 FSH membrane
receptor
(through cAMP)
Testis(sertoli cells)
Mature sperm cell
+
Spermatocyte increase
Progesterone
(corpus luteum)
 LH + mebrane
receptor
(through cAMP)
Testosterone
(leyding cells)
o maturity of ovary follicule
o conversion of ruptured follicules to corpus luteum
 GnRH is essential for the secretion of intact FSH and
LH, feedback from estradiol and testosterone plus
gonadal peptides such as inhibin have a secondary
effect
 Feedback by estradiol can have negative or positive
effects on gonadotrophins ,depending on the stage of
menstrual cycle
 Both FSH and LH concentrations vary considerably
depending on age and sex
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HUMAN CHORIONIC
GONADOTROPHIN(hCG)
 Glycoprotein synthesized in the syncytrotrophoblast
cells of the placenta
 Resembles LH
 Increases in blood and urine shortly after implantation
 The basis of pregnancy tests
POSTERIOR PITUITARY HORMONES
 Antidiuretic hormone(ADH)(VASOPRESSIN)
 Nonapeptide, containing cysteine molecules
 To promote reabsorption of water from the distal renal
tubules
 Primaly synthesızed in the supraoptic
nucleus,transported through axons with
neurophysins(neurophysin II)
 Circulates unbound to proteins
 Increased osmolality of plasma (mediated by
osmoreceptors in the hypothalamus, by baroreceptors
in the heart and other regions of vascular system) is
the primary physiologic stimulus
 Other stimuli: emotional and physical stress,
acetylcholine, nicotine,morphine
 Hemodulition has the opposite effects
 Epinephrine and ethanol inhibit ADH secretion
 In the absence of ADH, the urine is not concentrated
and may be excreted in amounts exceeding 2L/day
 ADH permits osmotic equilibration of the collecting
tubule urine with hypertonic interstitium
 There are 2 types of ADH or vasopressin receptor:
 V1 extreranal
(activation of phospholipase C IP3 + DAG
Ca + activation of protein kinase C)
 A major effect of V1 receptors is vasoconstriction and
increased peripheral vascular resistance
V2 on the surface of renal epithelial cells
(cAMP dependent)
 cAMP and inhibitors of phosphodiesterase activity
(caffeine) mimic the actions of ADH
PATHOPHYSIOLOGY
 Abnormalities of ADH secretion/action
Diabetes Insipidus(DI)
excretion of large amounts of dilute urine
 Primary DI;
 insufficient amounts of hormone,
 may be due to the destruction of hypothalamic-
hypophysial tract(a basal skull fracture, tm, infection)
 Hereditary nephrogenic DI;
 ADH secretion is normal
 A receptor defect (+)
 Acquired nephrogenic DI;
 Mostly due to pharmacologic administration of
lithium for manic-depressive illness
 Inappropriate secretion of ADH;
 Ectopic production by tumors(usually lung), brain
diseases, pulmonary infection, hypothyroidism
 ADH is produced at a normal or increased rate in the
presence of hypoosmolality
persistent and progressive dilutional hyponatremia
with excretion of hypertonic urine
OXYTOCIN
 Nonapeptide, containing cysteine molecule
 Physylogical role is to promote milk ejection from the
mammary gland (by stimulating contraction of
myoepithelial cells around mammary alveoli)
 To stimulate uterus smooth muscle contraction
induce labor
 Synthesized in the PVN, transported through axons in
association with neurophysin I
 Neural impulses from stimulation of nipples are the
primary stimulus
 Vaginal and uterine distention are secondary stimuli
 PRL is released by many of the stimuli that release
oxytocin .
 Estrogen stimulates and progesterone inhibits
oxytocin and neurophysin I production
 Receptors are found in both uterus and mammary
tissues
(upregulated by estrogen
down regulated by progesterone)