Estrogens &progestinSynthesisGonads & adrenal glandsFunctionsConception, embryonic maturation &

development of primary & 2ndary sexual characteristic during puberty & are used therapeutically

1) Natural Estrogens (human, female)Steroid in natureEstradiol (17-β-estradiol, major & most potent)

Estrone (E1)= 1/10 potentEstriol (E3)= 1/10 potent

2) Synthetic EstrogensSteroidal = Ethinyl estradiol, mestranol & quinestrol

Non-steroidal= Diethyl stilbestrol & chlorotrianisene,

HYPOTHALAMUS

GnRH

ANT. PITUITARY

FSH LH

ESTROGEN PROGESTERONE

OVARY

Dysmenorrhea (painful menses)

Primary hypogonadism (estrogen-deficient patients) Postmenopausal hormone therapy ( hot flushes,

muscle cramps, anxiety, over breathing)

Osteoporosis

Contraception

Other uses (intractable dysmenorrhea, hirsutisim & amenorrhea; excessive secretion of androgens by ovary)

. Impaired glucose tolerance (hyperglycemia)

Increase incidence of breast, vaginal and cervical cancer

Nausea & breast tenderness (minimized by dose)

HyperpigmentationMigraine headacheGall bladder disease, cholestasisCardiovascular — most concern a. Thromboembolism b. Hypertension

1) Natural ProgestinsProgesterone (humans, i.m. ; ineffective orally)

2) Synthetic Progestins Medroxyprogesterone acetate Hydroxyprogesterone acetate (i.m) Norethindrone tablets Norgestrel Desogestrel

For Contraception (alone or +estrogen)

Hormonal replacement therapy of postmenopausal women (combination)

Secondary amenorrhea, uterine bleeding disorders, leuteal phase support to treat infertility and premature labour

1. Nausea, vomiting 2. Headache 3. Fatigue, depression of mood 4. Menstrual irregularities 5. Weight gain (fluid retention) 6. Hirsutism 7. Masculinization (Norethindrone) 8. Ectopic pregnancy

9. Acne and/or oily skin

10. Loss of sex drive (Libido)

Drugs or Devices used for prevention of pregnancy

Condoms (sheath-male & female)

Female sterilization (surgical blockade of fallopian tubes)

Vasectomy (surgical sealing of vas)

Cap (rubber sheath; females)

Pill (tablet= E+P)

Mini-pill (progesterone only pill; POP)

cont.

Long acting Hormonal Methods Contraceptive implants

(implanted on skin contains hormone)

Mirena (IUS; T-shaped contains progesterone)

Coil (IUD; hormones) Contraceptive injections Contraceptive patch (sticky patch; hormones)

1. Fertility awareness

2. Withdrawal

3. Lactational amenorrhea method

4. Sympto-thermal method

5. Ovulation method ( Mucus method )

6. Calendar method

Hormonal contraceptive cause Reversible suppression of fertility at will

Over 100 million women worldwide use hormonal contraceptives

Oral Parenteral

Implanted

a) Combination Injectable skin

(E+P) Medroxyprogesterone

Norgestrel

b) Minipill (Progestins) i.m; oily sol. Slow release of

steroid

c) Post coital contraception (E or combination)

a) Combination pillsEstrogen + Progestin

MOA E+P inhibit ovulation P bleeding at end of cycle E+P blocks carcinoma

cont.

i) Monophasic combination tabletsE (ethinyloestradiol or mestranol)+P (norethisterone or

desogestrel; 0.5-1mg) Most popular & most effective e.g., Loestrin, Desogen, Brevicon, Ovcon

Method1 tab daily for 21 consecutive days gap of

7 days (bleeding)to maintain cycle of 28 days

To keep low total steroid dose Recommended for Women > 35 y Constant Estrogen dose (varied slightly; 30-40 g) Progestin = low in first phase in 2nd phase (normal

cycle)

Two typesBiphasic

Triphasic

1st Phase = Days = 1-10 (one set of tablets)2nd Phase= Days = 11-21 (conc. of progestin ; 2nd

set of tablets)e.g., Jenest, Ortho-Novum , Necon

b) Triphasic combination tablets1st Phase = Days = 1-6 (6 days; one set of tablets)2nd Phase = Days = 7-11 (5 days; 2nd set of tablets)3rd Phase = Days = 12-21 (10 days; 3rd set of

tablets)e.g., Ortho-Novum, Tri-Norinyl, Ortho-tri-Cyclen

cont.

a) 1st Phase (6 days)Ethinyl estradiol (30 g) + Norgestrel (50

g)b) 2nd phase (5 days)Doses of E +P (mid cycle)c) 3rd phase (10 days)E (dose ); P (dose )d) Gap of 7 daysBleeding occurs

Estrogen (mg) Progestin (mg)

Monophasic combination tablets

Loestrin 21 1/20 Ethinyl estradiol 0.02 Norethindrone acetate

1.0

Desogen, Apri, Ortho-Cept Ethinyl estradiol 0.03 Desogestrel 0.15

Brevicon, Modicon, Necon 0.5/35 Ethinyl estradiol 0.035 Norethindrone 0.5

Demulen 1/35 Ethinyl estradiol 0.035 Ethynodiol diacetate

1.0

Nelova 1/35 E, Ortho-Novum 1/35 Ethinyl estradiol 0.035 Norethindrone 1.0

Ovcon 35 Ethinyl estradiol 0.035 Norethindrone 0.4

Demulen 1/50 Ethinyl estradlol 0.05 Ethynodiol dlacetate

1.0

Ovcon 50 Ethinyl estradlol 0.05 Norethindrone 1.0

Ovral-28 Ethinyl estradiol 0.05 D,L-Norgestrel 0.5

Norinyl 1/50, Ortho-Novum 1/50 Mestranol 0.05 Norethindrone 1.0

Biphasic combination tablets Jenest-28, Ortho-Novum 10/11, Necon 10/11, Nelova

10/11

Days 1—10 Ethinyl estradiol 0.035 Norethindrone 0.5

Days 11—21 Ethinyl estradlol 0.035 Norethlndrone 1.0

Triphaslc combination tablets

Triphasil, Tri-Levlen, Trivora

Days 1—6 Ethinyl estradlol 0.03 L-Norgestrel 0.05

Days 7—11 Ethinyl estradiol 0.04 L-Norgestrel 0.075

Days 12—21 Ethinyl estradiol 0.03 L-Norgestrel 0.125

Ortho-Novum 7/7/7, Necon 7/7/7

Days 1—7 Ethiriyl estradiol 0.035 Norethindrone 0.5

Days 8—14 Ethinyl estradiol 0.035 Norethindrone 0.75

Days 15—21 Ethinyl estradiol 0.035 Norethindrone 1.0

Ortho-TrI-Cyclen

Days 1—7 Ethinyl estradiol 0.035 Norgestimate 0.18

Days 8—14 Ethinyl estradiol 0.035 Norgestlmate 0.215

Days 15—21 Ethinyl estradiol 0.035 Norgestimate 0.25

Estrogen (mg) Progestin (mg)

Progestin (norethisterone, ethynodiol or norgestrel)

MethodDaily without interruption Indications for POP When it is desirable to eliminate estrogen:

During breast feeding (estrogen suppress postpartum lactation)

Contraindications to estrogen (e.g. hypertension or breast cancer) Smokers more than 35 years old

Slightly higher failure rate (efficacy 97%) Less reliable contraceptive effect Inconsistent suppression of ovulation incidences of Breakthrough bleeding Should be taken every day, 365 days of the year &

at the same time each day even during menstruation Oral tablets Name Progestin (mg)

Micronor ----- Norethindrone 0.35 NOR —---- ----- Norethindrone 0.35 Ovrette ----- dl- Norgestrel 0.075

Regimen Timing of 1st dose after intercourse

Reported efficacy

100 µg ethinyl estadiol & 0.5 mg levonorgestrel (Yuzpe regimen) given twice, with 12hr between doses(total 4 tab.)

Within 72hrs 75%

High-dose of estrogen (e.g., 50 µg ethinylestradiol daily for 5 days)

Within 72 hrs 75 - 85%

Mifepristone (a single dose of 10, 50 or 600 mg) ±Misoprostol (400 µg)

Within l20 hrs 85 - 100%

Intramuscular injection

e.g. Medroxyprogesterone acetate 150 mg, i.m every 3 months

3. Implantable progestin preparation

e.g. Norplant — L- Norgestrel (6 tubes of 36 mg each; 5 years protection )

A) MOA Interfere fertility by:i) Inhibition of ovulationE= feed back inhibition of FSH inhibit

folliclesP = inhibit secretion of LH inhibit ovulationii) Inhibition of implantationAlteration of endometrium (by alteration of

hormones) = inhibit implantation of fertilized ovum cont.

Progestins=thick & viscid cervical secretion less conductive for passage of sperm

iv) Hypermotility of Fallopian tube & Uterus

a) Fallopian Hypermotility= rapid passage of ovum to uterus + prevents normal fertilization

b) Uterus Hypermotility= expelling of fertilized ovum (Postcoital contraception)

Chronic use of HC ovarian function

Morphological changesi) Follicular development is minimalii) Absence of corporal lutea, larger

follicles, stromal edema iii) Smaller size of ovariesiv) Majority= normal Menstural Cyclev) 2% = Amenorrhic for several years

i) Hypertrophy of cervix (prolonged use)ii) Polyp formationiii) Thickening of cervical mucus = less

copiousiv) glandular atrophy + less bleeding ( E)

Clinical uses of Contraceptives As contraceptive Treatment of endometriosis (E+P) Severe dysmenorrhea (E alone; suppression of

ovulation)

Thromboembolic phenomenon, cardiovascular & cerebrovascular disorders

Vaginal bleeding (unknown cause) Avoided in tumor of breast or other E-dependent

neoplasm Avoid in =Liver disease, asthma, eczema, migraine,

diabetes, HTN, optic neuritis, or convulsive disorders

Vomiting and diarrheaDrugs interfere with absorption ( eg. Ampicillin )Inducers of hepatic enzymes ( eg. Barbiturates,

phenytoin )

Drugs fertility in females by:

Maturation of ovarian follicles (e.g., HMG)

Ovulation induction (e.g. clomiphen; HCG)

Reduction of excessive prolactin level (e.g., bromocriptine)

Control of endometriosis (e.g., GnRH)

E.g., Antiestrogens (clomiphene & tamoxifen), Gonadotropin Releasing Hormone (GnRH; e.g. Leuprolin, goserlin), Human Menopausal Gonadotropin (HMG) & Bromocriptine

a) Clomiphene Citrate

Partial agonist at Estrogen receptor (has mixed agonist and antagonist activity)

Mechanism of fertility promotionBlocks Estrogen receptors on hypothalamus &

pituitary (oppose –ve feed back of E) FSH & LH stimulation of ovary= promotion of follicular maturation & induce ovulation

Used in treating infertility caused by lack of ovulation

Conditions Normal & functioning pituitary & ovary If follicular maturation but no ovulation =HCG is

added to regimenSuccess rate:

- Ovulation = 80% - Pregnancy = 40% Method

50 mg/d for 5 days from day 5th of the cycle to 10th

if no response:- 100 mg/d for 5 days from day 5th to 10th

1. Hot Flushes 2. Gastric upset (nausea and vomiting)

3. Visual disturbances (reversible)

4. Skin rashes 5. Increase nervous tension 6. Depression 7. Fatigue 8. Weight gain 9. Breast tenderness, heavy menses10. Hair loss (reversible) - occasional 11. Hyper stimulation of the ovaries and high incidence of multiple birth

Competitive partial agonist inhibitor of estradiol at estrogen receptors

First selective SERM

Extensively used in palliative treatment of breast cancer in postmenopausal women

Similar & alternative to clomiphene Non steroidal agent & given orally

Pulsatile GnRH =stimulate LH & FSH releaseSustained non pulsatile GnRH = inhibit LH & FSH release GnRH= decapeptide found in all mammalsSynthetic analogues= Leuprolin, goserelin

Uses: Induction of ovulation in patients with hypothalamic amenorrhea (GnRH deficient),

Cont…..

GnRH and agonists, given S.C. in a pulsatile (drip) form to stimulate gonadotropin release (1 – 10 µg / 60 – 120 min)Given continuously, when gonadal suppression is desirable e.g. endometriosis, precocious puberty and advanced breast cancer in women and prostatic cancer in menSide effects of GnRH agonists: Hypo-oestrogenism (long term use), Hot flushes, Decreased libido, Osteoporosis

Hormonal preparation having LH & FSH activity Commercially prepared by extraction from

postmenopausal urine

Therapeutic uses1) Female infertility

HMG+HCG=promote follicular maturation & ovulation Used when gonadotropins from pituitary is insufficient

2) Male infertility (hypogonadotropic hypogonadism, idiopathic male infertility)

Adverse effects: Fever, ovarian enlargement (hyper stimulation), multiple pregnancy (approx. 20%), gynecomestia (occasional )

Polypeptide hormone produced by placentaPolypeptide hormone produced by placenta Similar in structure & actions to luteinizing Similar in structure & actions to luteinizing

hormone (LH)hormone (LH)Uses Uses (adjunct in treatment of infertility)(adjunct in treatment of infertility)

a) HCG+HMGa) HCG+HMGInduce ovulation by stimulating mid cycle LHInduce ovulation by stimulating mid cycle LH

surge in infertile females (surge in infertile females (follicular maturation must be follicular maturation must be induced by HMG)induced by HMG)

b) HCG + Clomiphen

Promote ovulation if clomiphene (alone) is failed

Adverse effects: Headache, edema & gynecomestia (males)

Ergot alkaloidUsesCorrect amenorrhea & infertility (when prolactin is )Mechanism of fertility promotionStimulate DA receptors (in ant pit) inhibition of

prolactin normalization of Menstrual cycle +fertility

Adverse Effects. Nausea, vomiting, dizziness, orthostatic hypotension,

constipation, dry mouth, leg cramps, insomnia, nasal congestion