The Endocrine

System

Hypothalamus-pituitary axis

The hypothalamic – Pituitary---end organs pathways

• Corticotrophin-releasing hormone. (CRH) causes a release of ACTH—Adrenal cortex—Mineralocorticoids, androgens.

• Gonadotrophins-releasing hormone. (GnRH). Causes a release of LH and FSH—estrogens, progesterone, Testesterone.

• Thyrotrophin-releasing hormone. (TRH) releases TSH– thyroid—T3.

• Somatostatin (GHIH). Inhibits the release of growth hormone.

• Somatorelin(GHRH).Release the growth hormone (GH, somatotropin)– IGF, somatomedines.

• Dopamine– prolactin---breast.

The pituitary Gland• Consists of anterior and posterior

lobes.

Anterior pituitary hormones

• They are regulated either by releasing or inhibiting factors or hormones.

• All are given either IM, IV or intranasally.

• They are not given orally (destruction by proteolytic enzymes).

1. Growth hormone (GH).

2. Prolactin.

3. Gonadotrophins (LH and

FSH).

4.Adrenocorticotrophic

hormone (ACTH).

5.Thyroid stimulating

hormone (TSH).

A. Growth hormone (somatotropin)

• It is a polypeptide with large MW.

• Released in response to GHRH by the

hypothalamus. Hypothalamus secret a growth – hormone releasing factor (GHRF) and a growth- hormone release inhibiting hormone—somatostatin).

• Secretion is high in the new born, decreasing at 4 years and maintained until after puberty, when there is a further decline.

• Released in pulsatile manner, highest during sleep.

• Stimulated byStimulated by: Hypoglycemia, Fasting and stress.

• Inhibited byInhibited by: insulin-like growth factor I and II (IGF-I, II), glucose, protein and corticosteroids.

• GHGH is produced by recombinant DNA technology.

Effects of GH 1. Stimulation of normal

growth and development.

2. Stimulate the production from the liver of several polypeptide mediators, IGFs (somatomedines) responsible for most anabolic actions.

3. Promote protein synthesis, and the uptake of amino acids into cells ( skeletal muscles and cartilage at the epiphyses of long bones), thus influencing

bone growthbone growth..

•Deficiency of GH causes retardation of growth in children- DWARFISM (due to lack of GHRF or IGF generation or action)

• GH is produced synthetically by recombinant DNA technology.

In short stature, a linear growth can be achieved by given SOMATOTROPIN S/C or IM, divide in 6-7 doses per week.

•SOMATRIM equal to GH, induces the release from the liver of IGF1(responsible for GH-like effects).

• Both have a Half-life 25 min

• Cleared by the liver

•It should not be given if the epiphysis is closed or suspected intracranial tumour or in acromegaly.

GH over secretion produces

a. Gigantism in children.

b. Acromgegaly in adults.

Somatostatin• ( Growth hormone-inhibiting hormone)

•Inhibits the release of GH, TSH, insulin, glucagon and gastrin.

•OCTREOTIDEIs a synthetic analogue of somatostatin.

Long acting (T1/2 80 min), depot preparation.Used in acromegaly and pituitary adenomas, tumours secreting vasoactive intestinal peptide, carcinoid tumours and esophageal varices.

Given S/C with peak action in 2h last 8h.

may cause:

• Pain at the site of injection• GIT upset• Gallstones ( 20-30%)• Hyperglycemia• Hepatitis

B. Prolactin• Is a peptide hormone

similar to GH

• Secreted by the anterior pituitary (lactotroph or mammotroph cells which are increased in pregnancy due estrogen).

• Secretion is inhibited by dopamine.

• Stimulated by suckling, TRH, oxytocin and estrogens

Actions 1. Mammatrophic - for normal

development and maturation of the mammary gland.

2. Lactogenic: during pregnancy

prolactin secretion is high and the level rise steadily towards term.

It play a part in milk production.

3.3.BehavioralBehavioral: prolactin rises in stress, sleep, decreases sexual

drive and orgasm.

Hyperprolactinaemia may lead to:

Impotence,

Hypogonadism, Gynaecomastia, Galactrorrhoea, Amenorrhea.

Treated by BROMOCRIPTINE and CABERGOLINE

Prolactin itself is not used clinically.

Bromocriptine• Is a dopamine receptor agonist.

• It acts like prolactin inhibitory factor and stimulates inhibitory dopamine

receptors, thus inhibiting prolactin secretion.

In acromegaly it suppresses GH release.

• Given Orally.

• 90% absorbed via the small intestine.

• Metabolised in the liver.

• Excreted via bile.

• T1/2 – 66 hours.

Uses 1. Puerperal lactation

can be suppressed.

2.5mg twice/d for 2 weeks. If breast tenderness 2.5mg for 1 week.

2. Hyperprolactinaemia

13% of cases of secondary amenorrhea

It may present as infertility, hypogonadism,

Galactrorrhoea occurs in 30% of patients.

• In men-causes impotence and decrease in volume of semen.

• 2.5-7.5mg twice daily for up to 6 months.

3. In the treatment of acromegaly.

4. Parkinson’s disease.

Adverse effects

1. Constipation, nausea and vomiting, peptic ulcers.

2. Postural hypotension , dizziness, cardiac arrythmias.

3. Headache.

4. Nasal congestion, dry mouth vascular spasm, cramps in the legs, pains in extremities, visual hallucination, Cardiac arrhythmias, alcohol intolerance.

5. Psychiatric problems (confusion, hallucination).

C.Gonadotrophins

•Gonadotrophin-releasing hormone (GRH)-gonadorelin

• Is essential for the release of FSH and LH.

• Used to stimulate gonadal hormones production in hypogonadism.

• Given IV and S/C• T1/2: 4 min

• May cause : allergy, dermatitis and headache.

Synthetic analogs:

LEUPROLIDEGOSERELINHISTRELINNafarelinBuserelinGiven S/C, Nasal spray, IMT1/2: 3h

They act as inhibitors of GnRH.

Used in prostatic cancer, endometriosis and precocious puberty.

May cause hot flushes, sweating, decrease libido, depression, osteoparosis and ovarian cysts.

1. Follicle-stimulating hormone (FSH).

•Is a glycoprotein.

•Secreted in the first part of menstrual cycle from the anterior pituitary.

• Stimulate the development of follicle (ovarian).

• Stimulate granulosa cell. Increase oestrogen production.

• In males stimulate spermatogenesis.

Is controlled by Luteinising hormone releasing hormone. (LHRH).

2. Luteinising hormone (LH).

• Is a glycoprotein. • Secreted in the second part

of menstrual cycle.• Induces ovulation.

• Maintains a corpus luteum (progesterone secretion).

• In males it stimulate androgen synthesis, and testosterone secretion (play a role in secondary sexual characteristics).

3. Human chorionic gonadotrophin

(HCG).

• It is derived from the urine of pregnant women which has an actions similar to LH.

•MENOTROPINSMENOTROPINS ( human menopausal gonadotropins, hMG)- obtained from the urine of menopausal women, contains FSH and LH.

•Chorionic Chorionic gonadotropins (hCG), placental hormone, LH agonist, excreted in urine.

•UROFOLLITROPIN:UROFOLLITROPIN: FSH devoid of LH, obtained from menopausal women.

•FILLITROPIN BETAFILLITROPIN BETA: human FSH, produced by recombinant DNA technology.

•All are given IM

•hMG and FSH causes ovarian follicular growth and maturation, followed by injection of HCG ovulation occurs.

• In men hCG causes external sexual maturation followed by hMG spermatogenesis occur.

Clinical uses1. Amenorrhoea and infertility

due to gonadotrophin deficiency ( causes ovulation to occur).

2. In polycystic ovary syndrome.

3. May correct defective spermatogenesis in secondary testicular failure.

4. HCG for 6 weeks may be used in the treatment of Undescended tests.

• Over treatment may result in enlargement of ovaries, cyst formation, pleural effusion, ascites, changes in blood volume and clotting mechanisms.

Clomiphene (Clomid)

An antioestrogen, blocks oestrogen receptors in the hypothalamus.

• Stimulate Gonadotrophins secretion.

• Used in treatment of subfertility in the females inducing ovulation with multiple births. 3mg/kg day for 7-10 days can assist in the diagnosis of secondary hypogonadism (causing increase in FSH and LH if the hypothalamus in intact).

AdrenocorticotrophiAdrenocorticotrophic Hormone (ACTH)c Hormone (ACTH)(Corticotrophin)(Corticotrophin)

Is a Polypeptide:• Its release is meditated by corticotrophin releasing factor (CRH).

• Stimulates Glucocorticoids, Mineralocorticoids and androgens secretion from adrenal cortex.

• Diurnal rhythm in its secretion being high in early morning(6 am) and low at midnight.

IndicationsIndications::• Are those of from

corticosteroids.

• The degree ACTH is unpredictable.

• The hormone may be destroyed by proteolytic enzymes.

• T1/2 : 20 min

• Used for diagnostic purposes in adrenocortical insufficiency.

COSYNTROPIN (synthetic human ACTH)

Adverse effectsAdverse effects::1. Acne, skin pigmentation,

increase bruising.

2. Sodium retention.

3. Hypertension.

4. Less growth retardation than corticosteroids.

5. Hypertrophy of adrenal cortex.

Posterior Pituitary Hormones

A. Vasopressin (antidiuretic hormone ADH)

Released into circulation by:

1.Increase in osmotic pressure.

2.Decrease in blood volume ( hypotension).

3.Drugs-morphine, nicotine.

4.Physical and emotional stress.

• It acts on the distal tubules and collecting ducts of the kidney.

• Increases water reabsorption.

• Causes vasoconstriction.

Uses: 1.Diabetes insipidus.2.Nocturnal enuresis (reduce

night urine production)

3. Bleeding from esophageal varices.

Preparations: • DesmopressinDesmopressin long acting,

selective for V2 receptors( renal tubule cells) synthetic preparation, given intranasally, effective for 24 hours.

• Drug of choice in D. insipidus.

B. Oxytocin• An octapeptideAn octapeptide

Produces contractions of the smooth muscle (from fundus to cervix) of the uterus and of the mammary gland ducts.

• Release from the pituitary following, suckling, emotional stimuli, and cervical dilatation.

• Given orally it is destroyed.

• Given parentrally.

• Has short t ½ -5-10 min.

• At labour it is given by infusion in normal saline at a rate of 5-20 milliunits /min( the amplitude and the frequency of contractions are dose dependent)

• May cause uterine rupture and water retention, hypertension, allergy and GIT upset.

ERGOMETRINEERGOMETRINE• Semi synthetic derivative of

alkaloid ergometrine produces powerful uterine contraction.

• Used to prevent and treat postpartum haemorrhage.

•Given 200 Mg IM or IV

Contraindicated in the first and second stage of labour.

•SyntometrineSyntometrine::•Is a mixture containing 5 units of oxytocin and o.5 mg ergometrine in 1 ml.

•Given IM or IV

Uses:

•Used for uterine contraction after delivery of the placenta.

Adverse effects

1. Powerful uterine contractions.

2. Rise in B.P.

3. Water retention3. Water retention.

Should not be combined with prostaglandins to induce labour.

The Thyroid• Consists of two lobes connected

by an isthmus.

SECRETESSECRETES:

• 1. Thryroxine (T4).

• 2. Tri-iodothyronine (T3)-most

active

3 .Calcitonin( serum calcium lowering hormone).

• T4, T3 secretion is controlled by pituitary thyroid-stimulating hormone : (TSH)- glycoprotein synthesized in the anterior pituitary.

• Hypothalamic thyrotrophin- releasing hormone (TRH).

• TSH increases the vascularity, size and cellularity of the gland, and accelerates synthesis and release of the thyroid hormones.

IODINEIODINE •The gland concentrate iodine from plasma iodide. Diet, water or drugs contains 100-200mg per day iodide, which rapidly absorbed from the stomach and intestine, taken up by the gland, oxidize to iodine by peroxidase

•followed by iodination of tyrosines on thymoglobulin. Condensations of two diiodotyrosine forms T3 or T4, which are bound to thryroxine binding globulin in the plasma.

• The gland taken up iodide for hormone production, and the rest is removed by the kidneys.

• Used to treat simple non-toxic goiter due to iodine deficiency.

Thryroxine and T3Actions and pharmacokineticsActions and pharmacokinetics:

• T3, T4 are bound to thryroxine-binding globulin (TBG).

• The potency of T3 is greater than T4(3-5 times)

• T4 is converted to T3.

FUNCTIONSA.Those affecting the

metabolism.

B. Those affecting the growth and development.

1.1. Stimulation of metabolismStimulation of metabolism

(carbohydrates, fat and proteins) resulting in a

a. raised metabolic rate, hyperglycemia

b. increased protein synthesis

c. increase of cardiac, rate and output, contraction, cardiac failure with tendency to atrial fibrillation, and angina.

2. Promotion of normalPromotion of normal growth and maturation (CNS and skeleton), through increase in growth hormone production, and response to parathormone and calcitonin.

3. Possibly sensitizationPossibly sensitization to the effects of catecholamines.

• T4 is absorbed well from GIT, food, calcium, aluminum containing antacids interfere with the absorption.

• T3 is not affected by food and is completely absorbed.

• T4 metabolized by CYP 450 inhibitors or inducers-(Phenytoin, rifampin, Phenobarbital….) enhances the clearance of T4.

T4 is converted to T3 in the tissues.

•Effect after 24h and maximum at 7-10 days.

•T3 effect within 6 hours.

•T1/2 of T4 – 6-7 days,T3-2 days.

They undergo enterohepatic circulation.

Abnormalities in thyroid functions

1.Hypothyroidism (myxoedema)

2.Hyperthyroidism (Thyrotoxicosis)

HypothyroidismHypothyroidism

•Due to either failure of the TRH-TSH release or insufficient of iodine (simple goiter).

•Symptoms

• Mental impairment.

• Deep, slow speech

• Bradycardia.

• Dry skin.• Sensitivity to cold.

PreparationsPreparationsSynthetic:Synthetic:• Levothyroxine (T4, thyroxine

sodium)-low cost, long half-life and given once daily..

• Liothyronine (T3,triiodothyronine)- for emergency( short T1/2, costly with increase in cardiotoxicity).

USES

•In uncomplicated hypothyroidism.

•Maintenance dose

• ( thyroxine) 100-200 mcg daily .

Adverse effects

• Sudden death due to ventricular fibrillation, angina, MI.

• Tachycardia, atrial fibrillation

•CCF can be precipitated.

•Diarrhoea.

•Tremor, restlessness, nervousness

• Allergy

•Weight loss• menstrual irregularities.

Hyperthyroidism Thyrotoxicosis

• High T3 and T4.

• Raised temperature and sweating.

• Tremor and nervousness. Fatigue.

•Tachycardia.

•Weight loss and increase in appetite.

•Protrusion of the eyeballs.

TreatmentPurpose:a.Reduce synthesis

and activityb.Reduction in

hormone effects.

Approach1.Use drugs that change tissue response to T. hormones.

2. Destroy the gland with surgery or radiation

a. Aqueous iodine solution.

b. Radio-iodine I131.

c. Thioamides (Thioureylenes)

Inhibition of TH synthesis

Thioamides

Carbimazole - Methimazole

• Most commonly used.

• Hydrolyzed to Methiamazole in plasma.

• Methimazole compete with iodide and inhibit the oxidation of iodine.

• It prevents T3, T4 synthesis by interfering with tyrosine iodination.

• Rapidly absorbed.• T1/2 varied –6-15 hours, given

once daily.• Metabolised in the liver and

thyroid.• Crosses the placenta and

excreted in milk.• Excreted in urine

USES •In hyperthyroidism in children under 18 years and in pregnant women.

• Response in 1 month( until thyroglobulins stores are depleted) and euthyroid in 4 months.

Adverse effects • The most important is Granulocytopenia (reversible)

• Nausea, loss of hair, rashes( 3-12%).

• Drug fever, arthralgia.

• Should be used with care in pregnancy.

Propylthiouracil

• Similar action, uses and toxic effects to carbimazole.

• Prevent the conversion of T4 to T3.

•Absorbed rapidly.

•T1/2 –2 HOURS.

•Crosses the placenta and found in milk.

•It can be given in pregnancy

BetaBeta Adrenergic Adrenergic BlockersBlockers

Propranolol or

calcium channel blockers

( Deltiazem)

• They reduce the followingThey reduce the following:

a. Resting tachycardia.

b. Anxiety

c. Sweating.

d. Termor.

e. Prolong the hyperactive reflexes.

Radioactive iodine

131 I is the radioactive isotope

It is converted to iodide in vivo, which inhibits the release of thyroid hormones over a period of 10-14 days.

• Effective oral treatment, rapidly absorbed (symptoms subside in 1-2 days).

• Incorporated into thyroid follicles.

Decreases the vascularity of the gland, becomes smaller and firmer. ( used before surgery) and destruction of the gland within few

weeks.

Problem in calculating the dose

7% of patients require thryroxine after 5 years.

• Iodine solution in potassium iodide is given orally

• 131 I with t1/2 of 8 days is used.

• May cause allergic reactions

• Should be avoided in children and pregnant and lactating women.