Endocrine

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 Endocrine

The endocrine system is composed of many organs (glands) which secrete

hormones

* Endocrine glands:
* They are glands that secrete hormones directly into blood:
Pituitary- Thyroid - Parathyroid - Suprarenal (cortex & medulla) - Islets of
Langerhans (endocrine pancreas) - Pineal glands (secrete melatonin), gonads
(testis and ovaries).

* Other organs with endocrine functions:

(1)Heart: secretes ANP (atrial naturetic peptide).
(2)Kidney: secretes erythropoietin, renin & 1-25 dihydroxycholecalciferol.
(3)Liver : secretes somatomedins & 25 dihydroxycholecalciferol.

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(4)Skin: secretes calciferol (vit D3).
(5)Gastrointestinal tract: gastrin, secretin, CCK, VIP (local action).

* Nervous & Endocrine inter-relation:

(1)Hypothalamic hypophyseal portal circulation: that transports
releasing or inhibiting factors that secreted from hypothalamus to reach
anterior pituitary (Vascular connection).

(2)Hypothalamic-hypophyseal tract: that transports ADH & oxytocin.

- These hormones are synthesized in supraoptic (ADH) & paraventricular

(oxytocin) nuclei in hypothalamus.

- Then transported down the axons of these neurons to their endings in

posterior lobe of pituitary where they are stored.

- They are secreted (when needed) in response to electrical activity in the

endings (Nervous connection).

Hormones:
* Definition: chemical substances secreted by special cells & affect
distant organs.
* Functions of hormones:
(1) Regulation of biochemical reactions

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(2) Regulation of body processes e.g. growth, maturation, regeneration,
reproduction and pigmentation.

*Chemical nature of hormones:

1) Simple amino acids (tyrosine derivatives)

1- Thyroid hormones

2- Catecholamines

2) Protein, polypeptide & glycoprotein

1-Hypothalamic releasing & inhibitory factors.

2-Pituitary hormones.

3-Parathyroid hormones.

4-Pancreatic hormones.

5-Thyrocalcitonin.

3) Steroid hormones

1-Adrenal cortical hormones (cortisol, aldosterone).

2-Gonadal hormones (estrogen, progesterone, testosterone).

3-Vitamin D derivatives.

*Mechanism of action of hormones:

After hormone secretion, it circulates in blood. Then, it reaches target cells
and bind to the receptors.

*Characters of cell receptors:

1-Specific: each receptor is highly specific for a single hormone. The relation
between hormone and receptor is like lock & key.

2-Dynamic: the number of receptors increases & decreases in response to

various stimuli.

3-Location: the site of receptor differs from hormone to hormone. It may be

on cell membrane or nucleus or in cytoplasm.
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(a)Polypeptide, proteins & glycoprotein hormones:

Their receptors are on the cell membrane because they are:

-Big molecules

-lipid insoluble

So, Not penetrate the cell membrane

(b)Steroid hormones

- Their receptors are in cytoplasm as they are:

- Lipid soluble & penetrate the cell membrane.

(c)Thyroid hormones

- Their receptors are in the nucleus. They are Lipid soluble & penetrate the
cell membrane & pass through nuclear pores & transcribe mRNA.

[A] Mechanism of hormones acting on cell membrane receptors

"Protein, Polypeptide & glycoproteins” “Non genomic”

• It is rapid mechanism (few minutes)

• After binding of the hormone to the membrane receptors, the active

hormone receptor complex act through one of the following pathway:

(1)Adenyl cyclase pathway (2)Inositol triphosphate & diacylglycerol

(1)Adenyl cyclase pathway:

* Formation of cAMP as 2nd messenger

a-The hormone (ligand) (first messenger) binds to the receptor. The

receptor is coupled to G protein.

b- G protein binds to and activate adenyl cyclase enzyme which convert ATP
to cAMP (second messenger).

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c- cAMP activates protein kinase which activates enzymes and produce
intracellular physiologic effects.

d-Termination of activity occurs by phosphodiesterase (PDE) that transforms

cAMP to 5 AMP (PDE is inhibited by theophylline & caffeine).

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(2)Inositol Triphosphate & diacylglycerol (IP3 & DAG ) pathway:

• The hormone (ligand) (first messenger) binds the receptor.

• The receptor binds to G protein.

• G protein activates the phospholipase C complex.

• This complex generates inositol triphosphate (IP3) and diacyl glycerol

(DAG) (IP3 & DAG: are second messengers)

• IP3 Release Ca from endoplasmic reticulum to induce enzymatic reactions &

physiologic effects.

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• DAG (diacyl glycerol) activates protein kinase C to induce enzymatic
reactions and physiologic effects.

[B]Mechanism for hormones acting on cytoplasmic or nuclear

receptors: Genomic action i.e. transcription of nuclear DNA

(1) Steroid Hormones: suprarenal – gonadal – 1,25 DHCC

(2)Thyroid hormones

There is delay for the beginning of action of steroid hormones for minutes,
hours or even days for full activation to appear

a. Steroid hormones enters the cytoplasm through the membrane (they are
lipid soluble) to bind with specific receptor present in the cytoplasm.

b. The combined hormone-receptor complex passes through the cytoplasm,

and then diffuses to the nucleus.

c. The complex activates specific genes (DNA) and form messenger RNA
which acts as second messenger.

d. mRNA diffuses into the cytoplasm where it helps the translation process at
the ribosomes to form new proteins which act as enzymes

e. The receptors for thyroid hormones are in nucleus..( the same mechanism )

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Pituitary Gland (Hypophysis)

Small gland 1 cm in diameter that lies in sella turcica. It is connected with the
hypothalamus by the pituitary stalk (neck). It is divided into:

1-Anterior pituitary (adenohypophysis: glandular pituitary)

It is composed of :

1-Anterior lobe

2-Intermediate lobe

2-Posterior pituitary (Neurohypophysis)

Anterior pituitary (Adenohypophysis) is the Master for majority of

endocrine glands

It controls: - Thyroid glands

- Supra renal cortex

- Gonads

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Anterior pituitary secretes the following hormones:
(1) Growth hormone: Somatotrophic hormone: Somatotropine: it is
secreted by somatotropes (acidophils).

(2) Prolactin: it is secreted by mammotropes (acidophils).

(3) Thyroid stimulating hormone (TSH): Thyrotrophic hormone or
thyrotrophine: it is secreted by thyrotropes (basophils).

(4) Follicle stimulating hormone (FSH) & Luteinizing hormone (LH):

gonadotrophic hormone or gonadotrophine: secreted by gonadotropes
(basophils).

(5) Adrenocorticotrophic hormone (ACTH): Corticotrophic hormone or

corticotrophin: secreted by corticotropes (basophils).

Regulation of adenohypophysis function:

[1]Hypothalamic control

* Hypothalamus releases stimulating factors or releasing factors:

1. Thyrotropine Releasing hormone (TRH).

2. Follicle stimulating hormone releasing hormone (FRH).
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3. Luteinizing hormone releasing hormone (LHRH).
4. Corticotropin releasing hormone (CRH).
5. Growth hormone releasing hormone (GRH).

• Hypothalamus secretes inhibitory factors:

1. GH inhibitory hormone (GIH): called somatostatin

2. Prolactin inhibitory hormone: PIH (dopamine in nature)

[2]Feed back control:

It is the mechanism by which the endocrine system tries to maintain the level
of any hormone in blood nearly constant.
[A]Negative feedback: the most common type e.g. if hormone level in
blood is High, it stimulate endocrine gland to decrease its secretion and vice
versa.
-According to distance between site of hormone secretion & site of feedback
effect, it is classified into:
(a)Short short loop feedback (ultra short): hormone suppress its own
secretion e.g. hormone secreted from hypothalamus.
(b)Short loop feedback: hormone suppresses its releasing factor e.g. hormone
from anterior pituitary suppress its releasing factor from hypothalamus.
(c)Long loop feedback: hormone secreted by endocrine gland affects
hypothalamus & pituitary e.g. effect of cortisol on corticotropin releasing
factor (CRF) from hypothalamus & ACTH from pituitary.
(d)Long long loop feedback: e.g. hormone induces a metabolic response.
Then the metabolic response suppresses the hormone release.
[B] Positive feedback: less common
If hormone increases in blood, it stimulates gland to produce more hormone
from the gland e.g. Rise in estrogen leads to increase Luteinizing Hormone
(LH) and further increase in estrogen.

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 Growth Hormone (GH)
• Chemistry: polypeptide

• Origin: acidophils of anterior pituitary

• Transport:

1. free form : 50 %
2. bound form: bound to growth hormone binding protein (GHBP)

• Level: the average/24 hours is 5-8 ng in child & 2-4 ng in adult

❑ Functions of GH:

[1] Action on Growth:

• On viscera: It stimulates hypertrophy (increase size of cells) &

hyperplasia (increase number of cells). So, there is increase size of viscera
• On skeleton: It stimulates chondrogenesis→leading to growth of the
epiphysial cartilage & elongation of bone (increase stature). After puberty,
it increases thickness of all bones.
• Mechanism: Effect of GH on growth is mediated by: Somatomedins
Somatomedins: are polypeptides - secreted by liver and other tissues as
cartilage.
- They have insulin like action 1: stimulate oxidation of glucose
2: inhibit lipolysis
-The insulin like action is not suppressed by anti-insulin antibodies.

* The principal circulating somatomedins are:

1/Insulin like growth factor I (IGF-I): Somatomedin C. It is produced
by liver & chondrocytes.
2/Insulin like growth factor II (IGF - II): plays a role in fetal
development.
• Factors that decrease somatomedins:
1. Protein deficiency.
2. Untreated diabetes.
3. Glucocorticoid.

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[2] On protein metabolism: Anabolic

a) Increases protein synthesis.

b) Positive nitrogen balance.
c) Protein sparer

• Mechanism of its anabolic effect:

Increases uptake of amino acids by cells, increases formation & activity
of ribosomal RNA.

[3]On minerals Secondary to protein anabolism, GH causes mineral retention:

a) Stimulates gastrointestinal absorption of Ca++

b) Decreases Na+ & K+ excretion

[4] On carbohydrate metabolism:

GH is diabetogenic, it raises blood glucose level by:

a) stimulating glycogenolysis & gluconeogenesis.

b) Decreasing insulin receptors.
• Under high level of GH (e.g. GH secreting tumor) there is severe
hyperglycemia.

[5] On fat metabolism: GH is lipolytic and ketogenic: increase lipolysis

& ketone bodies formation and fatty acid oxidation.

• Control of GH secretion:

Factors that increase GH secretion

1) Growth hormone releasing hormone GRH: It stimulates GH

production from anterior pituitary
2) Insufficient calorie supply
− Acute: decrease blood glucose & free fatty acids (FFA)
− Chronic: fasting, starvation
− Physical stress & Exercise

3-Increase circulating amino acids

4-Start of sleep

5-Hormones: Estrogen
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Factors that inhibit GH secretion

1- Growth hormone inhibiting hormone GHIH (Somatostatin): It

inhibits GH production from anterior pituitary

2- Sufficient calorie supply

- Acute: hyperglycemia & increase FFA

- Chronic : obesity

3-Hormones: Cortisol & somatostatin

Disorders of anterior pituitary:

[1] Deficiency of GH: Pituitary Dwarfism

It is caused by decreased GH secretion before puberty

Characters & features:

1- Development of all features are diminished in relative proportions:

a-Arrested skeletal growth: ossification centers appear early and there is

rapid union of epiphysis.
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b-Symmetrical growth retardation: the height (from crown to toes) =
span (distance between outstretched fingers) & the distance from crown to
symphysis = distance from symphysis to toes.

C-Retardation of soft tissue growth

2- No mental retardation

3- Sexually normal

[2] Deficiency of GH and gonadotropins: pituitary infantilism

Dwarfism is accompanied by hypogonadism & failure of sexual
development.

[3] Deficiency of all hormones: Panhypopituitarism: Pituitary cachexia:

1- Premature senility: Premature graying of scalp hair - loss of body hairs-

Dry wrinkled skin- shrunken eye.
2- Pallor due to anemia & deficiency of ACTH & MSH (melanocyte
stimulating hormone)
3- Secondary manifestation of generalized endocrine hypofunction

[4] Gigantism: Increase GH before the closure of epiphysis of long

bone (before puberty)

• Features:

1. Overgrowth of all bones leading to tall individual (with normal body

proportions): growing period is lengthened; giant may continue to grow till
time of death usually at 22 years.
2- Overgrowth of soft tissue: Visceromegaly

3- Hypogonadism due to pressure of acidophil on basophil.

4- Hyperglycemia: pituitary diabetes (insulin resistant) in 25 % of cases

[5] Acromegaly: increase GH after closure of epiphysis (after puberty)

Features:

1-Overgrowth of bones: the bones become thicker. Because of epiphysis

fusion, there is only overgrowth of terminal portion of skeleton.

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 a- Overgrowth of bones of hands & feet.

b- Overgrowth of vertebrae lead to bowing of spines or kyphosis

c- Overgrowth of skull:

1- Large & elongated.

2- Supra-orbital ridges are prominent
3- Nasal bones: thick
4- Overgrowth of mandible → protrusion of mandible & separation of teeth.

2- Overgrowth of soft tissues & muscles

3-Hyperglycemia and diabetes mellitus (25 % of cases): it is pituitary

diabetes which is insulin resistant diabetes.

4-Diplopia and bitemporal hemianopia: in some cases as a result of

compression on the optic chiasma which lies in front of the pituitary
gland.

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 Prolactin Hormone

Origin: Acidophils of anterior pituitary (lactotropes).

Level in plasma: 8 ng/ml in female & 5 ng/ml in male.

Functions in females:

1- Milk secretion from breast after estrogen & progesterone priming.

2- It increases action of mRNA for synthesis of milk casein & lactalbumin.
3- It has insulin like action on breast (stimulates glucose utilization &
lipogenesis).
4- It prevents ovulation by inhibiting the effect of gonadotrophic hormones
(FSH & LH) on ovaries.
5- It causes anovulation (infertility) & amenorrhea during lactation.

Functions in male: enhance LH receptors in leydig cells to increase

testosterone hormone.

▪ Control (Regulation) of prolactin:

(1)Hypothalamus:

1-Prolactin is under tonic inhibition by hypothalamus.

2-Hypothalamus secretes prolactin inhibitory hormone (PIH) which is

dopamine in nature.

3- Negative feedback:
High level of prolactin stimulates PRL inhibitory hormone from hypothalamus
(dopamine) to decrease prolactin secretion.

(2)Sleep: prolactin rises at onset & persists at plateau.

(3)Stress: e.g. exercise & surgery.

(4)Suckling: causes rise with each nursing.

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(5)Pregnancy: it rises gradually to a peak at time of parturition.

(6)Parturition: it falls to original level 8 ng/ml

(7)Dopamine receptor blockers (antagonists): chloropromazine

stimulate prolactin. While dopamine & dopamine agonists (bromocryptine)
decreases PRL.

▪ Disturbances of PRL secretion:

(A) Hypoprolactinemia: rare.

(B) Hyperprolactinemia:

Cause: (1) Tumor of anterior pituitary: It secretes prolactin

(2) Dopamine blocking agents e.g. chloropromazine.

* Effects: it is a common cause of gonadal dysfunction because PRL inhibits

effects of gonadotrophins on gonads.

In female: infertility, amenorrhea, galactorrhea & decrease libido.

In male: infertility, impotence, gynecomastia, decrease libido

Treatment: Dopamine agonist (stimulating) drugs e.g. Bromocryptine.

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 Posterior Pituitary

It releases 2 hormones:

(1)Vasopressin: Antidiuretic hormone (ADH) (Pressophysin)

(2)Pitocin: Oxytocin (Oxyphysin).

o Origin: Their precursors are manufactured in supra-optic & paraventricular

nuclei in hypothalamus.

o Storage: They are packed in secretory granules

o Inactivation: in kidney & liver by vasopressinase & oxytocinase.

Antidiuretic hormone (ADH) (Vasopressin)

▪ Origin: mainly supraoptic nuclei & to a lesser degree paraventricular
nuclei.

▪ Chemistry: nanopeptide i.e. 9 amino acids.

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▪ Functions:

Through ADH receptors which are 3 types:

1-V1: in vascular smooth muscles.

2-V2: in renal tubules.

3- V3: in corticotropes of anterior pituitary.

[1]Renal effects:

a) It helps facultative water reabsorption in late distal tubules of kidney via

V2 receptors (decrease H2O loss).
b) It enhances K+ secretion.
c) It acts on V3 receptors in glomerular mesangium increasing
prostaglandin E2 (PGE2) which is vasodilator.
- ADH-PGE2 vasodilator antagonizes ADH-vasoconstrictor effect
maintaining renal perfusion.

[2]Extra-renal effects:

a- Vascular system: ADH in large dose causes vasoconstriction (VC)

leading to increase arterial blood pressure. Thus, it has a pressor effect in
hemorrhage & shock.

It cause constriction of visceral blood vessels & used to stop gastrointestinal

bleeding.
*Mechanism: it acts on V1 receptors

b- Anterior pituitary:

- It stimulates V3 receptors of corticotropes to increase ACTH.

- CRH is co-secreted with ADH from paraventricular nuclei. It stimulate
ACTH & cortisol to antagonize stress.

c- On brain: help memory.

d- It has 10 % of oxytocin action.

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Control (regulation) of ADH secretion:

[A] Factors Increase ADH:

(1) Increase plasma osmolarity: Increase osmotic pressure of

plasma 1% stimulates osmoreceptors in hypothalamus & ADH
secretion. ADH stimulates water reabsorption & osmolarity return to
normal.

(2) Hypovolemia: decrease blood volume by 10% affect ADH through

Arterial baroreceptors - Volume atrial receptors - Renin – angiotensin
system.

(3)Stress: through CRH-ADH system

(4)Nausea: stimulates ADH (unknown mechanism)

)5)Drugs: morphine, nicotine.

(6)Hot weather.

[B] Factors Decrease ADH:

Low osmolarity – Hypervolemia – alcohol & cold.

ADH deficiency (diabetes insipidus)

▪ Cause:

1-Damage of neurohypophyseal system

2-Nephrogenic diabetes insipidus: inability of kidney to respond to ADH due

to absence of receptors (V2).

Symptoms:

1- Polyuria: large volume of urine up to 10 liter /day.

-Low specific gravity of urine (1002 – 1003).

-Loss of H2O soluble vitamins & electrolytes.

-Tasteless urine (insipidus).

2-Polydipsia: drinking large volume of fluid.

3-Basal Metabolic Rate (BMR): increases as more volume of water are

heated.
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 Oxytocin (Pitocin)

▪ Functions:

(1)Milk ejection (milk letdown): Most important

It contracts myoepithelial cells around breast alveoli. Milk is squeezed out of

alveoli into ducts & baby obtains it by suckling.

(2)Uterine contraction: during labor to expel baby & placenta

(3)During sexual intercourse :

In male: contraction of vas deferens to ejaculate semen.

In female: contraction of myometrium to help sperm transport.

▪ Control :Neurohormonal reflex

(a)Suckling reflex: suckling stimulates touch receptors in the nipple to

cause reflex secretion of oxytocin.

(b) labor: cervical stimulation by the head of the fetus during labor causes
reflex secretion of oxytocin.

(c)Sexual intercourse: stimulation of female genital tract sends impulses

which cause oxytocin secretion.

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