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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 axis2- hypothalamo_pituitary_adrenal axis3- hypothalamo_pituitary_gonadal axis4-the growth hormone axis5-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 productSomatostatin 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 nucleotide-binding protein- cAMP

Somatostatin inhibits: TSH INSULIN

GLUCAGON GASTRIN

 Growth hormone(GH), prolactin and chorionic somatotropin(CS: plasental lactogen) constitute one hormone groupThey range in size from 190_199 amino acidsEach has a single tryptophan residueEach has 2 homologous disulfide bondsShare common antigenic determinants All have growth promoting and lactogenic

activity

                    GHSynthesized in somatotropes, a subclass of the

pituitary acidophilic cellsReleased 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 (during growth)

Protein synthesis RNA synthesis like insulin DNA synthesis

 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 lactogenesisGH 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 peptideHomology with proinsulinActs like a paracrin hormoneLiver 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 acidsHas activity similar/ identical to

multiplication stimulating activity(MSA)Plasma levels are twice those of IGF-1

 Clinical disorders of GH section pathophysiologyBasal 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 receptors2-PygmiesGH 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. lipsSpade-like hands Protruding jaw (prognathism)Sweatingİmpared 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:SurgeryLong acting somatostatin analogues

(octreotide )Pegvisomant (a GH antagonist)Radiation

Prolactin axis23KD a proteinHomologous to GH Secreted by lactotropes ,acidophilic cells in

the anterior pituitary The number of these cells and their size

increase dramatically during pregnancyİt 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 glycosylationThe number of TRH receptors are down

regulated bythyroid 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 rhythmTSH, like TRH, acts via a specific G_protein

coupled receptoradenyl cyclasecAMP dependent protein kinase

TSH controls every aspect of thyroid hormone biosynthesis and secretion :

iodide transportİodothyronine formationThyroglobulin proteolysisThyroxine 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-PITUITARY-ADRENAL AXISCorcototropin releasing factor(CRF)41 amino acid peptide secreted by PVNActs via G_protein coupled receptorcAMP second messenger system ; to stimulate

both synthesis and secretion of ACTHVasopressin(VP) potentiates the response of

the pituitary to CRHNegative 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-PITUITARY-GONADAL AXISGonadotropin 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 LHHas 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

FSH membrane receptor (through cAMP)

Follicular cells(ovary)growth of graff follicule

Testis(sertoli cells)

Mature sperm cell +Spermatocyte increase

LH + mebrane receptor (through cAMP)

o maturity of ovary follicule o conversion of ruptured follicules to corpus

luteum

Testosterone(leyding cells)

Progesterone (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 placentaResembles LH Increases in blood and urine shortly after

implantation The basis of pregnancy tests

POSTERIOR PITUITARY HORMONES

Antidiuretic hormone(ADH)(VASOPRESSIN)Nonapeptide, containing cysteine moleculesTo promote reabsorption of water from the

distal renal tubulesPrimaly 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

PATHOPHYSIOLOGYAbnormalities 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 normalA receptor defect (+)

Acquired nephrogenic DI;Mostly due to pharmacologic administration

of lithium for manic-depressive illnessInappropriate 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

OXYTOCINNonapeptide, containing cysteine moleculePhysylogical 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)