Anterior Pituitary Gland

S. Sh. Sadr MDS. Sh. Sadr MDProfessor of Tehran UniversityProfessor of Tehran University

Physiology DepartmentPhysiology Department

ObjectivesAfter studying this chapter, you should be able to: Describe the structure of the pituitary gland and how it

relates to its function. Define the cell types present in the anterior pituitary Understand the function of hormones derived from the

anterior pituitary Define the effects of the growth hormone in growth and

metabolic function, and how insulin-like growth factor I (IGF-I) may mediate some of its actions in the periphery

Describe the Regulation of Growth Hormone Secretion Understand the basis of conditions where pituitary

function are abnormal, and how they can be treated

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Adenohypophysis

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)hGH)

)PRL(

30 - 40

20

Hypothalamic Releasing and Inhibitory Hormones Control Anterior

Pituitary Cells

GHRH TRH

Somatotroph Gonadotroph Thyrotroph Lactotroph Corticotroph

CRHGnRH PIH

GH LH & FSH TSH PRL ACTH, β-LPH, γ-LPH and β-Endorphin

SS

- -- -

Somatostatin or GHIH

Dopamine or PIH?

SS

++ + ++

Glycoprotein family

POMC family

• 191 AA• t1/2 < 20 min

hGHhGH

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Circadian Rhythm of GH

06.00 12.00 18.00 24.00 06.00

hC

H i

n B

loo

dSleep

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Growth Hormone Has Several Metabolic Effects

(1) increased protein synthesis

(2) increased use of fatty acids for energy (3) decreased glucose utilization

Growth HormoneGrowth HormoneMetabolic effects

Proteins lipidsCarbohydrates

Growth effects Necessity of Insulin and Carbohydrate for the Growth-

Promoting Action of GH

• Stimulate Growth Hormone Secretion

Decreased blood glucoseDecreased blood free fatty acidsIncreased blood amino acids (arginine)Starvation or fasting, protein deficiencyTrauma, stress, excitementExerciseTestosterone, estrogenDeep sleep (stages II and IV)Growth hormone-releasing hormone

Ghrelin

Factors That Stimulate or Inhibit Secretion of GH

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• Inhibit Growth Hormone Secretion

Increased blood glucoseIncreased blood free fatty acidsAgingObesityGrowth hormone inhibitory hormone (somatostatin)Growth hormone (exogenous)

Somatomedins (insulin-like growth factors)

Factors That Stimulate or Inhibit Secretion of GH

GH Exerts Much of Its Effect Through Intermediate Substances Called "Somatomedins“

("Insulin-Like Growth Factors")

• GH stimulates liver, cartilage, skeletal muscle and bone to produce Somatomedin (Somatomedin C or IGF-1)

• Most effects of GH are mediated indirectly by somatomedins

• Direct action promotes lipolysis and inhibits glucose uptake

Direct & Indirect Actions of GH

Figure 15.6

Short Duration of Action of GH but Prolonged Action of IGF-1

Possible Role of Decreased GH in Aging

The average plasma concentration of GH

ng/ml 5 to 20 years 6 20 to 40 years 3 40 to 70 years 1.6

treatment of elderly patients with GH: insulin resistance and diabetes, edema, and joint pain.

Therefore, GH therapy is generally not recommended for use in healthy

elderly patients with normal endocrine function.

GH Stimulates Cartilage and Bone Growth

(1) increased deposition of protein by the chondrocytic and osteogenic cells

(2) increased rate of reproduction of these cells

(3) a specific effect of converting chondrocytes into osteogenic cells

thus causing deposition of new bone.

GH Stimulates the Osteoblast cells

Growth Factors

• Poly peptides

• Hormone like function

Growth factor

A growth factor is a substance that is capable of stimulating cellular growth,

proliferation and cellular differentiation.

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1-Neurotrophic Factors

• Nerve Growth Factor (N.G.F.)• 135000 D.• 7SNGF• 3 Chain α,β, γ• βN.G.F. Nerve Growth

Nerve growth factor (NGF)nerve growth factors refers to a family of

factors also known as neurotrophins.NGF circulates throughout the entire body and

is important for maintaining homeostasisis critical for the survival of sensory neurons.

Without it, these neurons undergo apoptosis.NGF causes axonal growth, axonal branching

and a bit of elongation

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Clinical significanceNGF: prevents or reduces neuronal degeneration in

neurodegenerative diseases promote peripheral nerve regeneration in rats The expression of NGF is increased in inflammatory

diseases where it suppresses inflammation promote myelin repair. Hence may be useful for the

treatment of multiple sclerosisDysregulation of NGF signaling has also been linked to

Alzheimer's disease.

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2-Epidermal G.F. and related F.

• E.G.F.• 53 aa• Transforming G.F.(T.G.F.)• α T.G.F. like E.G.F.• β T.G.F. like Inhibin

Epidermal growth factor (EGF ) found in many human tissues including submandibular gland,

parotid gland In addition to saliva, it can be found in human platelets,

macrophages, urine, milk, and plasma biological effects of Salivary EGF: maintenance of oro-esophageal & gastric tissue integrity. healing of oral and gastroesophageal ulcers, inhibition of gastric acid secretion, mucosal protection against intraluminal injurious factors such

as gastric acid, bile acids, pepsin, and trypsin and to physical, chemical and bacterial agents

stimulation of DNA synthesis

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3-Mitogen G.F.

• Platelet Derivate G.F. (P.D.G.F.)• 17000 D.• 2 Chain (A,B)• Fibroblast G.F. (F.G.F.)• 17000 D.• F.G.F. Angiogenesis

Fibroblast growth factors (FGFs)FGFs are multifunctional proteins with a

wide variety of effects; they are most commonly mitogens but also have regulatory, morphological, and endocrine effects.

They have been alternately referred to as "pluripotent" growth factors due to their multiple actions on multiple cell types.

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One important function of FGF1 and FGF2: is the promotion of endothelial cell

proliferation and the physical organization of them into tube-like structures.

They thus promote angiogenesis & vasculogenesis

FGF1 and FGF2 are more potent angiogenic factors than vascular endothelial growth factor (VEGF) or platelet-derived growth factor (PDGF)

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FGFs are important players in wound healing: FGF1 and FGF2 stimulate proliferation of fibroblasts

that give rise to granulation tissue, which fills up a wound space/cavity early in the wound-healing process.

FGF7 and FGF10 (also known as Keratinocyte Growth Factors KGF and KGF2, respectively) stimulate:

repair of injured skin and mucosal tissues by stimulating the proliferation, migration and differentiation of epithelial cells.

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During development of the CNS, FGFs play important roles in neurogenesis, axon growth, and differentiation.

FGFs are also important for maintenance of the adult brain.

Thus, FGFs are major determinants of neuronal survival both during development and during adulthood.

FGF-1 and FGF-2 seem to be involved in the regulation of synaptic plasticity and processes attributed to learning and memory, at least in the hippocampus.

Adult neurogenesis within the hippocampus depends greatly on FGF-2.

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4-Insulin like G.F.(I.G.F.)

• Somatomedin,M.S.A.,N.SI.L.A.• I.G.F.І or somatomedin C• I.G.F.II• Synthesis by Liver

Insulin-like growth factors (IGFs)

are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment

This complex system (often referred to as the IGF "axis") consists of :

two cell-surface receptors (IGF1R and IGF2R), two ligands (Insulin-like growth factor 1 (IGF-I) and

Insulin-like growth factor 2 (IGF-2)), a family of six high-affinity IGF-binding proteins (IGFBP-1 to

IGFBP-6), associated IGFBP degrading enzymes, referred to collectively

as proteases.

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The IGF "axis" is also commonly referred to as the Growth Hormone/IGF-I Axis

The IGF axis has been shown to play roles in: promotion of cell proliferation inhibition of cell death (apoptosis)

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Insulin-like growth factor 1 (IGF-1)also called somatomedin C

is a primary mediator of the effects of growth hormone (GH).

IGF-1 is a hormone similar in molecular structure to insulin.

It plays an important role in childhood growth and continues to have anabolic effects in adults.

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Synthesis and circulation

IGF-1 is produced primarily by the liver as an endocrine hormone.

Production is stimulated by growth hormone (GH) and can be retarded by:

undernutrition, growth hormone insensitivity, lack of growth hormone receptors, failures of the downstream signalling pathway post

GH receptor.

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Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding

IGF-1 binds to at least two cell surface receptors: the IGF-1 receptor (IGF1R) insulin receptor The IGF-1 receptor seems to be the "physiologic"

receptor - it binds IGF-1 at significantly higher affinity than the IGF-1 that is bound to the insulin receptor

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IGF-I acts as a neurotrophic factor, inducing the survival of neurons.

IGF-I has an involvement in regulating neural development including neurogenesis, myelination, synaptogenesis, and dendritic branching and neuroprotection after neuronal damage.

Increased serum levels of IGF-I in children have been associated with higher IQ.

IGF-I shapes the development of the cochlea through controlling apoptosis. Its deficit can cause hearing loss.

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Organs and tissues affected by IGF-ISince many distinct tissue types express the

IGF-1 receptor, IGF-1's effects are diverse:It may catalyse skeletal muscle hypertrophy, by

inducing protein synthesis, and by blocking muscle atrophy.

It is protective for cartilage cells, and is associated with activation of osteocytes, and thus may be an anabolic factor for bone.

Since at high concentrations it is capable of activating the insulin receptor, it can also complement for the effects of insulin

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Neuropathy:Therapeutic administration with neurotrophic

proteins (IGF I) is associated with potential reversal of degeneration of spinal cord motor neuron axons in certain peripheral neuropathies

Cancer:IGFs play a pathogenic role in diseases such

as cancer and diabetes, showing for instance that IGF-1 stimulates growth of both prostate and breast cancer cells

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Dwarfism:Laron dwarfism does not respond at all to growth

hormone treatment due to a lack of GH receptors. The FDA has grouped these diseases into a disorder

called severe primary IGF deficiency. Severe primary IGFD includes patients with

mutations in the GH receptor, post-receptor mutations or IGF mutations. As a result, these patients cannot be expected to respond to GH treatment.

People with Laron syndrome have strikingly low rates of cancer and diabetes.

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As a therapeutic agent

Mecasermin (brand name Increlex) is a synthetic analog of IGF-1 which is approved for the treatment of growth failure.

Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing hemoglobin A1C levels, as well as daily insulin consumption

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Insulin-like growth factor 2 (IGF-2)

The major role of IGF-2 is as a growth promoting hormone during gestation.

IGF-2 exerts its effects by binding to the IGF-1 receptor.

IGF2 may also bind to the IGF-2 receptor (also called the cation-independent mannose 6-phosphate receptor), which acts as a signalling antagonist; that is, to prevent IGF2 responses.

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In the process of folliculogenesis: IGF-2 is created by theca cells to act in an autocrine

manner on the theca cells themselves, and in a paracrine manner on granulosa cells in the ovary.

IGF2 promotes granulosa cell proliferation during the follicular phase of the menstrual cycle, acting alongside follicle stimulating hormone (FSH).

After ovulation has occurred, IGF-2 promotes progesterone secretion during the luteal phase of the menstrual cycle, together with luteinizing hormone (LH).

Thus, IGF2 acts as a co-hormone together with both FSH and LH.

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5-Blood Cells G.F.

• Erythropoietin• Glycoprotein• 18400 D.• 166 aa• Synthesis by Liver and kidney(adult)• G.M.Colony Stimulating F.(G.M.C.S.F.)• Glycoprotein• 23000D. ,106 aa

• Interlukin 1,2,3• IL 117500D.Peptide Synthesis by Macrophage• IL 2• Synthesis by T Lymphocyte• IL 3 (Multi C.S.F.)• Glycoprotein• 2 Chain• 28000D.

Dwarfism Decrease in GH Treatment with Human Growth Hormone Panhypopituitarism Levi-LorainPanhypopituitarism in the adultGigantismAcromegaly

Gigantism

Gigantism & Dwarfism

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AcromegalyAcromegaly

Acromegaly

Charles Sherwood Stratton and Lavinia Warren Stratton

Tom Thumb

Prolactin (PRL)

: ماموتروپین، الکتوژنیک، دیگر اسامیلوتئوتروپیک

آمینه 199دارای اسید

رشد هورمون به زیاد شباهت

: عمر دقیقه 30تا 20نیمه

: کلیوی، فیلتراسیون حذف نحوهرسپتوردر واسطه با اینترنالیزاسیون

کبدی های سلول

اثر حاملگی هنگام در استروژنمهار پستان در را پروالکتین الکتوژنوزیس

کند .می

Prolactin (PRL)• In females, stimulates milk production by the

breasts• Triggered by the hypothalamic prolactin-

releasing hormone (PRH)• Inhibited by prolactin-inhibiting hormone (PIH)• Blood levels rise toward the end of pregnancy• Suckling stimulates PRH release and encourages

continued milk production

DP & PRL

TSH• Glycoprotein• 28,000 d weight• Stimulates all of TH synthesis steps• TSH injection causes T3 and T4 release within

30 min.• The most early effect of TSH injection is ↑ TG

proteolysis• Second messenger = cAMP

Long Loop

Long Loop

Cortisol

CortisolCortisol

Adrenal

Corticotroph

ACTH

CRHHYPOTHALAMUS

CRH Cortisol

Short Loop

STRESS - Infection - Trauma - Surgey

Sleep/wake

ACTH

Hypoglycemia

Figure 5

-MSH

Circadian Rhythm of ACTH release

Boron and Boulpaep “Medical Physiology”

ACTHنقشناشی • ترشح وهم گلوکوکورتيکوئيد پايه ترشح بر هم

دارد دخالت ازاسترس

سبب VIPوازوپرسين،• قشرآدرنال بر اثر با وسروتونينترشح شوند ACTHافزايش می

•ACTH مقادير به قشرآدرنال وحساسيت پاسخ افزايش سبب.ACTHبعدی گردد می

•ACTH حداکثرترشح زوددارای درصبح فورانی بصورت. است ترشح حداقل ودرشب

ترشح • بطورانحصاری ACTHافزايش استرس با درمقابلهو هيپوتاالموس است.CRHازطريق

Effective factors On ACTH Secretion

1 .StressHypoglycemia,Trauma,Surgery,Infection,Anesthesia))

2.CRH Decreased Cortisol . 34 .Sleep5 . ADH

Thanks For Your Attention