Dr. Areej M. Al-Taweel Pharmacognosy Department Pharmacognosy Department.

Dr. Areej M. Al-TaweelDr. Areej M. Al-Taweel

Pharmacognosy Pharmacognosy DepartmentDepartment

HormonesHormones Definition:Definition: Natural secretionNatural secretion of the of the

endocrine system endocrine system

that exert important that exert important functional effectsfunctional effects upon upon other tissuesother tissues

in minute concentrations.in minute concentrations.

Endocrine system:Endocrine system: Composed of group of Composed of group of glands glands

called called “Endocrine glands”.“Endocrine glands”.

Endocrine glands:Endocrine glands: Glands that pour their Glands that pour their secretion secretion

directly to the blood.directly to the blood.

Components of the Endocrine Components of the Endocrine SystemSystem

Hypothalamus:Hypothalamus: Located at the base of Located at the base of the brain. It secretes the brain. It secretes Releasing Releasing and and InhibitingInhibiting hormones that target the hormones that target the Anterior pituitary glandAnterior pituitary gland and control its and control its secretions.secretions.

Hypothalamic hormones include:

TRH: Thyrotrophin-releasing hormone CRH: Corticotrophin- releasing hormone GnRH: Gonadotrophin- releasing hormone

PIH: Prolactin-inhibiting hormone probably dopamine.

PRH: Prolactin-releasing hormone. GHIH: Growth hormone- inhibiting hormone

( Somatostatin ) GHRH: Growth hormone-releasing-hormone.

These hormones are carried to the anterior pituitary by the

hypothalamo-hypophyseal portal system.

Secretions of the anterior pituitary are also regulated by the feedback (usually negative feedback) exerted by target gland hormones.

* The Hypothalamus is directly above the pituitary

gland is connected to the posterior pituitary (neurohypophysis) by the pituitary stalk.

* The Hypothalamus is connected with anterior pituitary (adenohypophysis) through the hypophyseal portal system.

* The pituitary gland is the master gland regulating the function of several other endocrine glands.

Pituitary gland:

Anterior Pituitary gland:Anterior Pituitary gland: Secretes Secretes hormones that control the secretion of the hormones that control the secretion of the other endocrine organs such as adrenal and other endocrine organs such as adrenal and thyroid glands. thyroid glands.

Thyroid Adrenal Gonads

A. A. Anterior pituitary hormones are Classified into:Anterior pituitary hormones are Classified into:

Somatotropic Hormones:Somatotropic Hormones:1- Growth Hormone (1- Growth Hormone (GHGH). ).

2- Prolactin (2- Prolactin (PrlPrl).).3- Placental Lactogen (3- Placental Lactogen (PLPL).).

Glycoprotein Hormones:Glycoprotein Hormones:1- Luteinizing Hormone (1- Luteinizing Hormone (LHLH).).2- Follicle-Stimulating Hormone (2- Follicle-Stimulating Hormone (FSHFSH).).3- Chrionic Gonadotropin (3- Chrionic Gonadotropin (CGCG).).4- Thyroid-Stimulating Hormone (4- Thyroid-Stimulating Hormone (TSHTSH).).

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

1- Corticotrophin: 1- Corticotrophin: ACTHACTH..2- Melanocyte-Stimulating Hormones: 2- Melanocyte-Stimulating Hormones: -MSH, -MSH,

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

B. The posterior pituitary releases:

-Antidiuretic hormone (also called vasopressin)

- Oxytocin.

* Both of which are produced in the hypothalamus and transported

to the posterior pituitary by the hypothalamo-hypophyseal nerve tract.

The adrenal glands are located on the The adrenal glands are located on the superior surface of the kidney. superior surface of the kidney.

Adrenal gland

Adrenal CortexAdrenal Cortex Adrenal medulla

Gonads:Gonads:

The gonads secrete sex steroid hormonesThe gonads secrete sex steroid hormones::

A. A. Leydig cellsLeydig cells in the interstitial tissue of in the interstitial tissue of the testes the testes secrete testosterone and other secrete testosterone and other androgensandrogens..

B. B. Granulosa cellsGranulosa cells of the ovarian follicles of the ovarian follicles secrete estrogensecrete estrogen..

C. C. The corpus luteumThe corpus luteum of the ovaries of the ovaries secretes secretes progesteroneprogesterone,,

as well as estrogenas well as estrogen..

Pancreas:Pancreas:

The endocrine part of the pancreases, namely the islets of The endocrine part of the pancreases, namely the islets of Langerhans, contains: Langerhans, contains:

- - Alpha cellsAlpha cells that secrete that secrete GlucagonGlucagon - - Beta cellsBeta cells that secrete that secrete InsulinInsulin

Thyroid and Parathyroid glands:Thyroid and Parathyroid glands:

* * Thyroid glandThyroid gland:: - It located at the base of the neck. - It located at the base of the neck. - It is a highly vascular bilobed structure.- It is a highly vascular bilobed structure. - - The main hormones secreted by the thyroid gland are: The main hormones secreted by the thyroid gland are:

■■ Iodinated derivatives of Iodinated derivatives of TThyroxine (T4)hyroxine (T4) and and Triiodothyronin Triiodothyronin (T3).(T3).

■■ Calcitonin.Calcitonin.

* Parathyroid glands* Parathyroid glands:: -- Small structures embedded within the thyroid gland. - They secrete a parathyroid hormone (PTH) which promotes a rise in blood calcium levels.

Hypothalamic releasing/inhibiting hormones alter release of anterior pituitary's, which act

on other endocrine or target

Chemical Classification of Chemical Classification of HormonesHormones

A- Steroidal HormonesA- Steroidal Hormones::

11 - -AdrenocorticoidsAdrenocorticoids:: Glucocorticoids e.g. HydrocortisoneGlucocorticoids e.g. Hydrocortisone..

Mineralocorticoids e.g. AldosteroneMineralocorticoids e.g. Aldosterone . .

22 - -Sex HormonesSex Hormones:: Female sex hormones e.g. Estrogens and ProgestinsFemale sex hormones e.g. Estrogens and Progestins

Male sex hormones e.g. AndrogensMale sex hormones e.g. Androgens..

B- Amino acids derived hormones:B- Amino acids derived hormones: 1- 1- Hormones derived from Hormones derived from single amino acidsingle amino acid e.g. e.g. Thyroxin.Thyroxin.

2- Peptide hormones:2- Peptide hormones:ii- Only amino acids:- Only amino acids:

*Anterior Pituitary hormones*Anterior Pituitary hormones: : - - Prolactin - Growth Hormone - Placental lactogen.Prolactin - Growth Hormone - Placental lactogen. * Corticotropins:* Corticotropins: Adrenocorticotropic hormone ACTH.Adrenocorticotropic hormone ACTH. * Insulin* Insulin * Parathyroid hormone and Calcitonin* Parathyroid hormone and Calcitonin..

ii- Glycoproteins (Amino acids and sugars):ii- Glycoproteins (Amino acids and sugars):

**Anterior Pituitary Hormones:Anterior Pituitary Hormones: - Leuteinizing hormone (LH) -Follicle Stimulating hormone (FSH)- Leuteinizing hormone (LH) -Follicle Stimulating hormone (FSH) - Chorionic Gonadotropin (CG) -Thyroid Stimulating hormone (TSH).- Chorionic Gonadotropin (CG) -Thyroid Stimulating hormone (TSH).

Thyroid HormonesThyroid Hormones

Thyroid Gland:Thyroid Gland: Highly vascular flat structure.Highly vascular flat structure. Located at the upper portion of the Located at the upper portion of the

trachea.trachea. Composed of twp lobes.Composed of twp lobes.

Hormones of the Thyroid Hormones of the Thyroid gland:gland:

Thyroid gland secretes Thyroxin T4 and lesser amounts ofThyroid gland secretes Thyroxin T4 and lesser amounts of triiodothyronine (T3).triiodothyronine (T3).

Calcitonin. Calcitonin.

Thyroxin and Thyroxin and TiiodothyroninTiiodothyronin

* Structures: * Structures: Derived from single amino acid.Derived from single amino acid.

O CH2CH COOHNH2

I

II

I

HO O CH2CH COOHNH2

I

II

HO

Thyroxine Triiodothyronine

5'

Structure Activity RelationshipStructure Activity Relationship

Angle between the two aromatic rings must Angle between the two aromatic rings must be 120be 12000..

33’’-Monosubstituted molecules are more -Monosubstituted molecules are more active than 3active than 3’’, 5, 5’’-disubstituted ones.-disubstituted ones.

Triiodothyronin is 4 times more active than Triiodothyronin is 4 times more active than Thyroxin.Thyroxin.

33’’-Isopropyl derivative is 7 times more -Isopropyl derivative is 7 times more active than Thyroxin.active than Thyroxin.

Hypothalamus

Anterior Pituitary

Thyroid gland

Thyroxin & Triiodothyronin

Thyrotropine Releasing Hormone(TRH)

Thyroid Stimulating Hormone(TSH)

Regulation:Regulation:

Stimulation: TRH

Inhibition: -ve Feed-back mechanism.

When blood concentrations of thyroid hormones increase

above a certain threshold, TRH-secreting neurons in the hypothalamus are inhibited and

stop secreting TRH .

Actions of the Thyroid Actions of the Thyroid Hormones:Hormones:

Enhance growth and protein synthesis.Enhance growth and protein synthesis. Essential for the development of the nervous Essential for the development of the nervous

system.system. Increase oxygen consumption and basal Increase oxygen consumption and basal

metabolic rate.metabolic rate. Increase body temperature.Increase body temperature. Cardiovascular effect:Cardiovascular effect:

Increase heart rate.Increase heart rate. Increase force of contraction.Increase force of contraction. Increase cardiac output.Increase cardiac output.

Disorders of thyroid function include:

* Hypothyrodisim

- In infants, cretinism

- In adults this cause myxoedema

* Hyperthyrodisim either:

- Diffuse toxic goiter

- Toxic nodular goiter

Disorders of thyroid functionHypothyroidism in children (Cretinism)

Cretinism: Irreversible condition due to deficiency of thyroxin Irreversible condition due to deficiency of thyroxin

soon after birth.soon after birth.

Retardation in physical and mental developmentRetardation in physical and mental development.

Sign and symptoms of Cretinism:

- Mental retardation - Large head - Swollen eye lids - Flattened nose - Temperature below normal - Enlarged tongue - Grows very slowly. - Poor metabolism - Thick, dry, cool skin

Disorders of thyroid functionHypothyroidism (Adult)

Myxoedema:Myxoedema: Deficiency of thyroxin in adults due to:Deficiency of thyroxin in adults due to:

Removal of thyroid gland by surgery.Removal of thyroid gland by surgery. Destruction of the gland by Radioactive Destruction of the gland by Radioactive

Iodine.Iodine. Atrophy of the thyroid gland.Atrophy of the thyroid gland.

Symptoms of Myxedema: Symptoms of Myxedema: Muscle weakness.Muscle weakness. Slow heart rate and low cardiac output.Slow heart rate and low cardiac output. Dry cold and thick skin.Dry cold and thick skin. Brittle coarse hair.Brittle coarse hair. Puffy expressionless face.Puffy expressionless face. Decreased sweating Decreased sweating Increase body weight and body fatIncrease body weight and body fat

Treatment:Treatment: Thyroxin for life.Thyroxin for life.

eg. :L-Thyroxin sodium ( Synthyroid)

Goiter is an enlargement in the thyroid gland (Thyroid Goiter is an enlargement in the thyroid gland (Thyroid Hypertrophy).Hypertrophy).

Low level of thyroxin.Low level of thyroxin. High level of TSH.High level of TSH.

Note: It is important to understand that goiter is not cancer and that most goiters are, in fact, benign

GoiterGoiter

Causes:Causes: Lack of iodine in Lack of iodine in diet.diet.Treatment:Treatment: Iodine. Iodine.

Simple goiters are further classified as: * Endemic (colloid) * Sporadic (nontoxic).

Simple goiters are caused by an inadequate supply of thyroid hormone to meet the body’s need. The thyroid gland tries to make up for this deficiency by enlarging

Goiters can be classified as: * Simple or non toxic goiter * Hereditary

What causes goiter?Goiters have different causes depending on their type.

Sporadic goiters: have no known cause. Sometimes certain types of drugs, such as lithium or aminoglutethimide, can cause this type of goiter.

Endemic goiters: occur in people within certain geographic areas who do not get enough iodine in their diet (iodine is necessary to make thyroid hormone).

Hereditary factors also may cause goiters. * Age over 40 * Family history of goiter

Main symptoms of GoiterMain symptoms of Goiter

A swelling in the front of the neck. Difficulty breathing, coughing, wheezing Difficulty swallowing (due to compression of the

esophagus). Hoarseness. Dizziness when the arms are raised above the head.

1-Graves’ disease:1-Graves’ disease:Causes: an autoimmune disease (a disease in

which your body’s immune system mistakenly attacks your healthy body). In this case, the thyroid gland is attacked, which causes it to over stimulate and results in swelling of this gland.

Other diseases and conditions can also cause a goiter. These include:

- Enlargement in the thyroid gland (Thyroid Hypertrophy).- Increased pulse rate - Increased sweating- High body temperature and flushes. - Hair loss- Inflammation of the eyes - Swelling of the tissues around the eyes- Decrease in body weight and body fat - Nervous excitability - Muscle weakness - Protrusion of the eye ball

Symptoms:Symptoms:

2- Hashimoto’s disease: This is another autoimmune disease. In this case, the disease causes inflammation of the thyroid gland, which in turn, results in underproduction of thyroid hormones. Attempts by other hormones to stimulate the thyroid gland cause it to enlarge.

3- Thyroiditis: Inflammation of the thyroid gland itself can result in an enlargement of the thyroid gland. This can follow a viral illness

Toxic nodular goiter

- Due to a benign neoplasm or adenoma and may develop in patients with long-standing simple goiter.

Disease Due to HyperthyroidismDisease Due to Hyperthyroidism

A goiter only needs to be treated if it is causing symptoms.Treatments for an enlarged thyroid include: Radioactive iodine to shrink the gland, particularly if the thyroid is producing too much thyroid hormone

Surgery (thyroidectomy) to remove all or part of the gland.

Small doses of Lugol's iodine or potassium iodine solution if the goiter is due to iodine deficiency

Treatment with thyroid hormone supplements if the goiter is due to underactive thyroid

Treatments

Calcitonin Calcitonin Site of Secretion:Site of Secretion: Thyroid gland.Thyroid gland.

Structures:Structures: Peptide Hormones composed of 32 Peptide Hormones composed of 32 amino acid in amino acid in

single chain.single chain.

Regulations: Regulations: By calcium ion concentration:By calcium ion concentration:

When calcium ion concentration in When calcium ion concentration in plasma increase calcitonin plasma increase calcitonin concentration increase and concentration increase and Vic versaVic versa..

Physiological Functions:Physiological Functions: Hypocalcimic effect.Hypocalcimic effect. Direct inhibition of bone resorption.Direct inhibition of bone resorption.

Uses:Uses: Hypercalcimia involving removal of Hypercalcimia involving removal of

calcium from bones as in Paget’s disease.calcium from bones as in Paget’s disease.

Calcitonin Calcitonin

Parathyroid Hormone Parathyroid Hormone (PTH)(PTH)

Site of SecretionSite of Secretion:: Parathyroid gland.Parathyroid gland.

Structure:Structure: Peptide hormones composed of 84 amino acid in Peptide hormones composed of 84 amino acid in

single chain.single chain.

The parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels.

Regulation:Regulation: By calcium ion concentration:By calcium ion concentration:

When When calcium calcium ion concentration in plasmaion concentration in plasma decreasedecrease PTH PTH concentrationconcentration increase increase and Vic and Vic versaversa..

Physiological Functions:Physiological Functions: Hypercalcimic effect.Hypercalcimic effect. Stimulate mobilization of calcium from bones.Stimulate mobilization of calcium from bones. Increase calcium absorption from the intestine.Increase calcium absorption from the intestine. Decrease calcium excretion and enhance Decrease calcium excretion and enhance

reabsorption.reabsorption. Stimulate calcium retention by renal tubules.Stimulate calcium retention by renal tubules.

DisordersDisorders

Due to accidental injury to parathyroid glands during thyroid or neck injury. Patient are unable to maintain their serum calcium without calcium supplementation & develop hypocalcemia

Hypoparathyroidism:

Hyperparathyroidism: It is over activity of the parathyroid glands resulting in excess production of PTH

ClassificationPrimary hyperparathyroidism: over secretion of PTH which leads to hypercalcemia due to adenoma, or, rarely, carcinoma of the parathyroid glands.

Secondary hyperparathyroidism: occur in response to low calcium levels, as encountered in various situations such as vitamin D deficiency or chronic kidney disease.

In all cases, the raised PTH levels are harmful to bone, and

treatment is often needed.

Recent evidence suggests that:

Vitamin D deficiency/insufficiency plays a role in the development of hyperparathyroidism.

Tertiary hyperparathyroidism: result from hyperplasia of the parathyroid glands and a loss of response to serum calcium levels.

Calcimimetic DrugsCalcimimetic Drugs

These These drugs are used to control PTH drugs are used to control PTH release from parathyroid glands in patients release from parathyroid glands in patients with primary and secondary with primary and secondary hyperthyroidism, without increasing hyperthyroidism, without increasing calcium and phosphate levels. calcium and phosphate levels.

The most common side effects of The most common side effects of calcimimetics are mild or moderate nausea calcimimetics are mild or moderate nausea and vomiting.and vomiting.

E.g. Cinacalcet HCl “Sensipar”.E.g. Cinacalcet HCl “Sensipar”.

Growth hormone (GH)Growth hormone (GH)

Structure:Structure: It is a single polypeptide chain It is a single polypeptide chain

composed of 191composed of 191

amino acid residues. It has two amino acid residues. It has two disulfide bonds.disulfide bonds.

Growth hormone (GH)Growth hormone (GH) Secretion:Secretion:

Somatotrophs of the Anterior Pituitary.Somatotrophs of the Anterior Pituitary.

Level:Level: - - High in children.High in children. - Maximal during adolescence. - Maximal during adolescence.

- Lowest during adulthood.- Lowest during adulthood.

Regulation:Regulation: - Stimulation:

� Growth hormone releasing hormone (GHRH)

- Inhibition: Growth hormone inhibitory hormone (GHIH) (=somatostatin)

Function:

1- It acts on a variety of tissues to stimulate protein anabolism, lipolysis & hyperglycemia.

2- Promotes growth of tissues.

3- Regulate protein, lipid, CHO & mineral metabolism.

Disease Conditions Related to GHDisease Conditions Related to GH

Deficiency:Deficiency:* * DwarfismDwarfism ( hyposecretion of GH in children).( hyposecretion of GH in children).

Excessive Secretion:Excessive Secretion:* * GiantismGiantism (hypersecretion of GH in children): (hypersecretion of GH in children):

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

* * Acromegaly Acromegaly (hypersecretion of GH in adult):(hypersecretion of GH in adult):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 adrenal 2- Tumors of pancreas, lung or adrenal gland.gland.

Symptoms:Symptoms: Enlargements of extremities. Enlargements of extremities.

Dwarfism Dwarfism (hyposecretion of GH in children)(hyposecretion of GH in children)

Sign & symptoms:Sign & symptoms:

- - Children show no abnormalities of intellectual development.Children show no abnormalities of intellectual development.- - They appear much younger than their age, not only becauseThey appear much younger than their age, not only because they are short but because their facial feature & body they are short but because their facial feature & body proportions are immatureproportions are immature

Treatment:Treatment: - Exogenous GH- Exogenous GH

Sign & symptoms:

- Tall stature (up to 2 ½ meter).- Mild-to-moderate obesity (common).- Massive generalized organomegaly.- Soft-tissue hypertrophy.- Exaggerated growth of the hands and feet with thick fingers and toes.- Coarse facial features.- Die at early age, usually due to heart failure.

GigantismGigantism(hypersecretion of GH in children)(hypersecretion of GH in children)

AcromegallyAcromegally (hypersecretion of GH in adult)(hypersecretion of GH in adult)

Sign & Symptoms:

- Thickening of the palms of the hands and soles of the feet. - Enlargement of hands (ring size), feet (shoe size) and head (hat size). - Enlargement of forehead and jaw, spreading teeth, and enlarging tongue. - Arthritis. - Oily skin and excessive sweating. - Fatigue, depression. - Impotence, loss of libido.

Treatment of Acromegaly Treatment of Acromegaly

Transsphenoidal surgery to remove tumor.Transsphenoidal surgery to remove tumor. Radiation therapy usually follow the surgery.Radiation therapy usually follow the surgery. Drug Therapy:Drug Therapy:

1- Dopaminergic Agonists:1- Dopaminergic Agonists:

Bromocriptine (ParlodelBromocriptine (Parlodel®®).).

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

Octerotide (SandostatinOcterotide (Sandostatin®®).).

Prolactin (Prl)Prolactin (Prl)

Structure:Structure: It is a single polypeptide chain composed of 199 It is a single polypeptide chain composed of 199 amino acid residues. It has three disulfide bonds. amino acid residues. It has three disulfide bonds.

Secretion:Secretion: Prolactin is secreted by the anterior pituitary.Prolactin is secreted by 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.

Physiological Effects:

Breast developments and initiation of lactation.

Regulation:Regulation: Inhibited Prolactin release-inhibiting factor [PRIF] Inhibited Prolactin release-inhibiting factor [PRIF]

secreted by the hypothalamus is generally held to be secreted by the hypothalamus is generally held to be dopamine itself.dopamine itself.

The main stimulus for prolactin release is suckling.The main stimulus for prolactin release is suckling. No hypothalamic stimulation.No hypothalamic stimulation. Stimulated by TRH but this is of pathological importance.Stimulated by TRH but this is of pathological importance.

Disorders:

Hyperprolactinemia: hypersecretion of prolactin by lactotroph cells. Causes:

Tumors in the lactotrophes. Hypothyroidism associated with high level of TRH. Hypothalamus or Anterior Pituitary disorders.

Sympotoms: In females: Galactorrhea, Amenorrhea, Infertility. In males: Galactorrhea, Impotence, Infertility.

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

Gonadotropic HormonesGonadotropic Hormones

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

Structures: - They are glycoproteins.

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

Anterior Pituitary. CG secreted by the placenta. (7 days after ovulation) &

remains in the urine & blood of pregnant women up to the end of pregnancy

Regulation: Stimulation: Gonadotropin-Releasing Hormone from the

hypothalamus (GnRH). Inhibition: Feed back mechanism by sex hormones.

Physiological effects:

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

In Females: LH: Induce Ovulation and stimulate Progesterone production. FSH: Enhance production of Estrogen and development of

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 Ovulation.Prediction of Ovulation: LH 36 hr before Ovulation. Reproductive system disorder in males and females.Reproductive system disorder in males and females.

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

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

Function of CG & uses:Function of CG & uses:

1- Diagnosis of pregnancy1- Diagnosis of pregnancy

2- Diagnosis of ectopic pregnancy2- Diagnosis of ectopic pregnancy

3- Prediction of spontaneous abortion3- Prediction of spontaneous abortion