Anterior Pituitary Anterior Pituitary (Tropic, Adenohypophyseal) Hormones(Tropic, Adenohypophyseal) Hormones

They are Classified into:They are Classified into: Somatotropic Hormones:Somatotropic Hormones:

1- Growth Hormone (GH).1- Growth Hormone (GH).2- Prolactin (Prl).2- Prolactin (Prl).3- Placental Lactogen (PL).3- Placental Lactogen (PL).

Glycoprotein Hormones:Glycoprotein Hormones:1- Luteinizing Hormone (LH).1- Luteinizing Hormone (LH).2- Follicle-Stimulating Hormone (FSH).2- Follicle-Stimulating Hormone (FSH).3- Chrionic Gonadotropin (CG).3- Chrionic Gonadotropin (CG).4- Thyroid-Stimulating Hormone (TSH).4- Thyroid-Stimulating Hormone (TSH).

PPro-ro-OOpiopiommelanoelanoccortin (POMC) derived ortin (POMC) derived Hormones:Hormones:

1- Corticotropin: ACTH.1- Corticotropin: ACTH.2- Melanocyte-Stimulating Hormones: 2- Melanocyte-Stimulating Hormones: -MSH, -MSH, --

MSH.MSH.3- Lipotropins: 3- Lipotropins: -LPH, -LPH, -LPH-LPH

Growth Hormone (GH)Growth Hormone (GH) Structure:Structure: It is a single polypeptide chain It is a single polypeptide chain

composed of 191 amino acid residues. It has composed of 191 amino acid residues. It has two disulfide bonds.two disulfide bonds.

Secretion:Secretion:Somatotropes of the Anterior Pituitary.Somatotropes of the Anterior Pituitary.

Level:Level:High in children.High in children.

Maximal during adolescence.Maximal during adolescence.

Lowest during adulthood.Lowest during adulthood.

Measurments:Measurments:During 24 hours.During 24 hours.

After stimulation.After stimulation.

Regulation:Regulation:Stimulation: By Growth Hormone Releasing Stimulation: By Growth Hormone Releasing Hormone (GHRH).Hormone (GHRH).

Inhibition: By Somatostatin.Inhibition: By Somatostatin.

Physiological Physiological Effects:Effects:

Direct Effects:Direct Effects:1- Stimulation of Lipolyses (Hydrolyses of 1- Stimulation of Lipolyses (Hydrolyses of

Triglycerides).Triglycerides).

2- Stimulation of Hepatic glucose output.2- Stimulation of Hepatic glucose output.

3- Production of Insulin-like growth factors (IGF’s, 3- Production of Insulin-like growth factors (IGF’s, Somatomedins)Somatomedins)

Indirect Effects:Indirect Effects:Mediated by IGF-1:Mediated by IGF-1:

1- Increase cell numbers.1- Increase cell numbers.

2- Positive Nitrogen balance.2- Positive Nitrogen balance.

3- Increase Protein synthesis.3- Increase Protein synthesis.

Disease Conditions Related to Disease Conditions Related to GH:GH:

Deficiency:Deficiency:* Dwarfism.* Dwarfism.

Excessive Secretion:Excessive Secretion:* * Giantism:Giantism:

Due to tumor in somatotrpes in young Due to tumor in somatotrpes in young children children or adolescents.or adolescents.

* * Acromegaly:Acromegaly:Rare disease (3/Million).Rare disease (3/Million).Causes:Causes: 1- Benign tumor of Pituitary gland 1- Benign tumor of Pituitary gland

(90%).(90%). 2- Tumors of pancreas, lung or 2- Tumors of pancreas, lung or

adrenal gland.adrenal gland. Symptoms:Symptoms: Enlargements of extremities. Enlargements of extremities.

Treatment of Treatment of Acromegaly:Acromegaly:

Transsphenoidal surgery to remove Transsphenoidal surgery to remove tumor.tumor.

Radiation therapy usually follow the Radiation therapy usually follow the surgery.surgery.

Drug Therapy:Drug Therapy:

1- Dopaminergic Agonists:1- Dopaminergic Agonists:

Bromocriptine (Parlodel®).Bromocriptine (Parlodel®).

2- Synthetic Somatostatin analogs:2- Synthetic Somatostatin analogs:

Octeroide (Sandostatin).Octeroide (Sandostatin).

Uses of Growth Hormone:Uses of Growth Hormone:* Replacement therapy for children with GH * Replacement therapy for children with GH deficiency.deficiency.

* Administered by intramuscular or subcutaneous.* Administered by intramuscular or subcutaneous.

Sources:Sources:* Recombinant DNA technology.* Recombinant DNA technology.

Growth Hormone Releasing Growth Hormone Releasing HormoneHormone(GHRH)(GHRH) Structure:Structure:

Single polypeptide chain composed of 108 Single polypeptide chain composed of 108 amino acid residues.amino acid residues.

Function:Function: Stimulate the secretion of GH.Stimulate the secretion of GH.

Uses:Uses: Treatment of children with GH deficiency Treatment of children with GH deficiency

due to hypothalamic defects.due to hypothalamic defects.

Diagnoses of the cause of GH deficiency.Diagnoses of the cause of GH deficiency.

Prolactin (Prl)Prolactin (Prl) Structure:Structure: It is a single polypeptide chain composed of It is a single polypeptide chain composed of

199 amino acid residues. It has three disulfide bonds.199 amino acid residues. It has three disulfide bonds. Secretion:Secretion:

Lactotropes of the Anterior Pituitary.Lactotropes of the Anterior Pituitary. Level:Level:

Starts early in the fetal stages.Starts early in the fetal stages. Decline shortly after birth and remain low in males.Decline shortly after birth and remain low in males. In female increase with pregnancy reach maximum In female increase with pregnancy reach maximum

level at term and remains high during lactation.level at term and remains high during lactation. Regulation:Regulation:

Inhibited by Dopamine.Inhibited by Dopamine. No hypothalamic stimulation.No hypothalamic stimulation. Stimulated by TRH but this is of pathological Stimulated by TRH but this is of pathological

importance.importance.

Physiological Effects:Physiological Effects: Breast developments and initiation of Breast developments and initiation of

lactation.lactation.

Prolactin imbalance:Prolactin imbalance: Hyperprolactinemia:Hyperprolactinemia:Causes:Causes:

Tumors in the lactotropes.Tumors in the lactotropes. Dopamine antagonists.Dopamine antagonists. Hypothyroidism associated with high level of Hypothyroidism associated with high level of

TRH.TRH. Hypothalamus or Anterior Pituitary disorders.Hypothalamus or Anterior Pituitary disorders. Renal failure.Renal failure.

Sympotoms:Sympotoms: In females: Galactorrhea, Amenorrhea, In females: Galactorrhea, Amenorrhea,

Infertility.Infertility. In males: Galactorrhea, Impotence, Infertility.In males: Galactorrhea, Impotence, Infertility.

Treatment:Treatment:

Dopamine agonists: Bromocriptine Dopamine agonists: Bromocriptine (Parlodel®)(Parlodel®)

Gonadotropic Hormones:Gonadotropic Hormones: They were given this name due to their They were given this name due to their

effect on Gonads.effect on Gonads. They includes: They includes:

1- Luteinizing Hormone (LH).1- Luteinizing Hormone (LH).2- Follicle-Stimulating Hormone (FSH).2- Follicle-Stimulating Hormone (FSH).3- Chrionic Gonadotropin (CG).3- Chrionic Gonadotropin (CG).

Structures:Structures: They are glycoproteins. All glycoproteins are composed of They are glycoproteins. All glycoproteins are composed of

two subunits two subunits and and . The . The -subunit is similar in all -subunit is similar in all hormones and contain two N-linked oligosaccharide hormones and contain two N-linked oligosaccharide chains. The chains. The -subunit is specific for each hormone. In LH, -subunit is specific for each hormone. In LH, TSH it contains one N-linked oligosaccharide chain, while TSH it contains one N-linked oligosaccharide chain, while in CG and FSH it contain two N-linked oligosaccharide in CG and FSH it contain two N-linked oligosaccharide chains.chains.

Secretion:Secretion: LH and FSH are secreted from the Gonadotropes of the Anterior LH and FSH are secreted from the Gonadotropes of the Anterior

Pituitary.Pituitary. CG secreted by the placenta.CG secreted by the placenta.

Regulation: Regulation: Stimulation:Stimulation: Gonadotropin-Releasing Hormone from Gonadotropin-Releasing Hormone from

the hypothalamus (Gn RH).the hypothalamus (Gn RH). Inhibition:Inhibition: Feed back mechanism by sex hormones. Feed back mechanism by sex hormones. CG produced by placenta after fertilization.CG produced by placenta after fertilization.

Physiological effects:Physiological effects: In Males:In Males:

LH: LH: Stimulate production of androgens by Leydig cells.Stimulate production of androgens by Leydig cells. FSH:FSH: Enhance normal sperm production by Sertoli cells. Enhance normal sperm production by Sertoli cells.

In Females:In Females: LH:LH: Induce Ovulation and stimulate Progesterone Induce Ovulation and stimulate Progesterone

production.production. FSH:FSH: Enhance production of Estrogen and development of Enhance production of Estrogen and development of

follicles.follicles.

■ Uses:Uses: Diagnostic uses:Diagnostic uses:

Diagnosis of Pregnancy: CG in Urine or Blood.Diagnosis of Pregnancy: CG in Urine or Blood. Prediction of Ovulation: LH 36 hr before Prediction of Ovulation: LH 36 hr before

Ovulation.Ovulation. Reproductive system disorder in males and Reproductive system disorder in males and

females.females.

Therapeutic uses:Therapeutic uses: Male infertility.Male infertility. Female infertility.Female infertility. Cryptorchidism.Cryptorchidism.

Antagonists:Antagonists: Used as contraceptives.Used as contraceptives.

Gonadotropin-Releasing Gonadotropin-Releasing HormoneHormone

(GnRH, LHRH)(GnRH, LHRH) Structure:Structure: Polypeptide composed of 10 amino acid Polypeptide composed of 10 amino acid

residues.residues. Secretion:Secretion: Hypothalamic neurones with onset Hypothalamic neurones with onset of puberty.of puberty.

Uses:Uses: Stimulation of Gonadotropin Secretion:Stimulation of Gonadotropin Secretion:

Long-term pulsatile administration in cases of Long-term pulsatile administration in cases of deficiency.deficiency.

Suppresion of Gonadotropin Secretion: Suppresion of Gonadotropin Secretion:

Log-acting GnRH in a continuous fashion. This is Log-acting GnRH in a continuous fashion. This is required in:required in:

Prostate cancerProstate cancer Estrogen dependent breast cancers.Estrogen dependent breast cancers. Endometriossis.Endometriossis. Gonadotropin-dependent precocious puberty.Gonadotropin-dependent precocious puberty.

Analogs:Analogs: Gonadorelin HCl (Synthetic Human GnRH).Gonadorelin HCl (Synthetic Human GnRH).

Adrenocorticotropic HormoneAdrenocorticotropic Hormone(ACTH)(ACTH)

Structure:Structure: Peptide hormone composed of 39 amino acid Peptide hormone composed of 39 amino acid

residues.residues.

Function:Function: Stimulate the secretion of Corticosteroids.Stimulate the secretion of Corticosteroids. Necessary for the adrenal gland otherwise atrophy of the Necessary for the adrenal gland otherwise atrophy of the

gland takes place.gland takes place.

Control: Control: Feed-back inhibition by corticosteroids.Feed-back inhibition by corticosteroids.

Uses:Uses: Diagnoses of Adrenal insufficiency.Diagnoses of Adrenal insufficiency.

Steroidal HormonesSteroidal Hormones(Adrenocorticosteroids, (Adrenocorticosteroids,

Adrenocorticoids, Corticosteroids, Adrenocorticoids, Corticosteroids, Corticoids)Corticoids) Secretion:Secretion:

Adrenal cortex of the adrenal gland.Adrenal cortex of the adrenal gland.

Regulation:Regulation: Stimulation:Stimulation: ACTH. ACTH. Inhibition:Inhibition: Feed back Mechanism. Feed back Mechanism.

Classification of Classification of corticosteroidscorticosteroids

They are all C21 hormones.They are all C21 hormones.

Corticosteroids

GlucocorticoidsRegulate carbohydrates, lipids

and proteins metabolism

e.g. Hydrocortisone

MineralocorticoisControl electrolytes and water

balance

e.g. Aldosterone.

Numbering System of Numbering System of Steroidal ring:Steroidal ring:

HO

1

2

34

56

7

8910

1112

13

1415

16

17

18

19

2021

22 23 2425

26

27

O

Progesterone

O

O

O

17-Hydroxyprogesterone

OH

HO

O

Pregnenolone

HO

Cholestrol

Biosynthesis of Adrenocorticosteroids

O

O

11-Deoxycortisol

OH

HO

O

O

CortisolHydrocortisone

OH

HO

HO

O

O

21-Hydroxyprogesterone

HO

O

O

Corticosterone

HO

HO

O

CHOO

Aldosterone

HO

HO

Physiological Functions and Physiological Functions and Pharmacological Effects:Pharmacological Effects:

Carbohydrates and Proteins Metabolism:Carbohydrates and Proteins Metabolism: Stimulate glucose formation in the brain.Stimulate glucose formation in the brain. Decrease peripheral utilization of glucose.Decrease peripheral utilization of glucose. Promote storage of glucose in the liver.Promote storage of glucose in the liver. Promote gluconeogenesis.Promote gluconeogenesis.

Lipids Metabolism:Lipids Metabolism: Redistribution of body fat (Buffalo hump, Redistribution of body fat (Buffalo hump,

Moon face).Moon face). Enhance lipolyses of Triglycerides.Enhance lipolyses of Triglycerides.

Electrolyte and Water balance:Electrolyte and Water balance: Enhance reabsorption of sodium and water Enhance reabsorption of sodium and water

into plasma.into plasma. Increase urinary excretion of potassium.Increase urinary excretion of potassium.

Blood Picture:Blood Picture: Increase hemoglobin and Red blood cells.Increase hemoglobin and Red blood cells. Decrease white blood cells.Decrease white blood cells.

Anti-inflammatory effects:Anti-inflammatory effects: Suppress inflammations regardless to their Suppress inflammations regardless to their

cause.cause.

Immunosuppressive Effects:Immunosuppressive Effects: Decrease immunity as a result of decrease the Decrease immunity as a result of decrease the

WBC’s.WBC’s.

Cell Growth:Cell Growth: Retardation of cell division and cell growth.Retardation of cell division and cell growth.

Disease Disease States:States:

Addison’s disease:Addison’s disease: Rare syndrome 1/100,000 due to Hypoadrenalism.Rare syndrome 1/100,000 due to Hypoadrenalism. Causes:Causes:

Atrophy of adrenal gland.Atrophy of adrenal gland. Tuberculoses.Tuberculoses. Low level of ACTH.Low level of ACTH.

Symptoms:Symptoms: Weakness, fatigue, apathy, depression and irritability.Weakness, fatigue, apathy, depression and irritability. Anemia and low blood pressure.Anemia and low blood pressure. Loss of sodium and dehydration.Loss of sodium and dehydration. Hypersensitivity to Insulin.Hypersensitivity to Insulin. Hyper pigmentation.Hyper pigmentation. Nausea and vomiting.Nausea and vomiting.

Cushing’s disease:Cushing’s disease: Rare syndrome 2- 5/Million due to Hyperadrenalism.Rare syndrome 2- 5/Million due to Hyperadrenalism. Causes:Causes:

Tumor of the Adrenal Cortex.Tumor of the Adrenal Cortex. Tumor of the Pituitary gland.Tumor of the Pituitary gland.

Symptoms:Symptoms: Alteration of fat distribution.Alteration of fat distribution. Hypertension.Hypertension. Osteoporosis.Osteoporosis. Growth retardation.Growth retardation. Decrease Immunity.Decrease Immunity.

Conn’s syndrom:Conn’s syndrom: Causes:Causes:

Inability of adrenal cortex to carry out 17Inability of adrenal cortex to carry out 17-hydroxylation of -hydroxylation of pregnenolone. That leads to low level of Cortisol and high level pregnenolone. That leads to low level of Cortisol and high level of Aldosterone.of Aldosterone.

Symptoms:Symptoms: Hypertension.Hypertension. Alkalosis.Alkalosis. Polyuria.Polyuria. Edema.Edema.

PharmacokinetiPharmacokinetics:cs: Absorption:Absorption:

Well absorbed from all sites of administration.Well absorbed from all sites of administration.

Plasma Protein binding:Plasma Protein binding: 90% to albumin or globulin.90% to albumin or globulin.

Half life (tHalf life (t1/21/2):): 1- 1.5 hr.1- 1.5 hr.

Metabolism and Excretion:Metabolism and Excretion: Excreted in urine after glycosylation with Excreted in urine after glycosylation with

glucuronic acid.glucuronic acid.

O

O

OH

HO

HO

A B

C D

Structure-Activity Relationship

Essential for activity

1

2

3

4

5

9

10

19

18

11 13

14

16

17

1, 2 Double bond improve carbohydrate

metabolism to Na+ retention

-CH3 increaseglucocorticoid activity

6

-CH3 in Cortisol increase all activities

-CH3 in Prednisolone increase antiinflammatory activity

&Decrease Na+ retaining activity

9-Fluoro increase all activitiesF Br Cl

Essential for antiinflammatory activity& carbohydrate regulatory activity

12

-F increase all activities if no OH at C-17-F with 16dihydroxy--inactive compounds

CH3 or OH eleminate

Na+ retention activity

Essential for activity

Essential for antiinflammatory activity

Ether & esters increase antiinflammatory &

glucocorticoid activities

21

Halogen & halomethylene greatly increase Topical antiinflammatory activity