Estrogen, Anti estrogen,

Progestin and

Hormonal Contraseption

Dr. Rika Yuliwulandari, PhD

1

Female Sex Hormonal Steroids

CH3

OH

OH

CH3

OH

O CH3

OH

OH

OH

Estradiol Estrone Estriol Intramuscular (100%) intramuscular (33%) oral (1.6%)

(estr-1,3,5-triene-3,17b-diol) (3-hydroxy-estr-1,3,5-triene-17-one)

Natural Estrogens

CH3

CH3

CH3

O

O

Progesterone

(Pregn-4-ene-3,20-dione)

Natural Progestin

(?????)

Biosynthesis and Metabolism of Estradiol and Progesterone

OH

CH3

CH3

CH3

CH3

CH3

OH

CH3

CH3

CH3 O

CH3

CH3OH

O

CH3

OH

OH

OH

CH3

OH

O

CH3

OH

OH

cholesterol pregnenolone testosterone estradiol

estriol

Conjugation to glucuronides, sulfates, etc….

CH3

O

CH3

CH3

O

OH

6a-hydroxy metabolite

CH3

O

CH3

CH3

OH

20a/b-hydroxy metabolite

CH3

OH

CH3

CH3

OH

H

5b-metabolite

estrone

CH3

O

CH3

CH3

O

progesterone

4

Ovulation

ESTROGEN

5

Pharmacology • Function:

– Vagina, cervix, uteri, falopian tube

– ↑ Secret of vaginal discharge and

cervix

– Proliferation of endometrium

– Secondary sex development:

• Women: increase fat in gluteal,

smoothen skin, pubic and arm pit hair,

acne, breast, hyperpigmentation breast

areole and genital area

• Stop epyphyseal plate

– Adult woman: menstruation cycle

• Productive women

• Pubertal and pre menopause

6

• Other sources of estrogen:

– Equus: pregnancy --- 100 mg/day

– Ekuilin and ekuilenin

• Estrogen like:

– Flavon, isoflavon, chumesthan

derivate

7

• Other estrogen effects:

– Metabolism • Anabolic effects: retention of electrolyte, water,

nitrogen.

• High dose, renal failure, heart failure, geriatric,

malnutrition: oedem ---- stop tx

• Diabetes: intolerance in glucose oral/iv test

– Carcinogen • Early studies … tumors of breast, uterus, testis,

bone, kidney …

• Estrogen – progestin combination … standard

practice now:

– Increased total risk of breast cancer by 24%

• Theory:

– Carcinogenic actions due to trophic effects (cell

proliferation effects)

– Alternate theory … conversion to quinones ROS

DNA damage

8

Pharmacokinetic • Absorption:

– GI tr, mucose, intact skin

– Po, iv: absorption fast and complete

– Dissolve in oil

• Inactivation: liver

• Excretion: gall bladder--- enterohepatic cycle -

-- ren

• Woman:

– Half cycle: 25-100 ug/day

– Luteal phase: 10-80 mg/day

– Menopause: 5-10 ug/day

• Man: 2-15 ug/day

• Metabolisms

• Natural: fast

• Synthetic: slow

9

Therapeutic Uses

•Combination oral contraceptives:

• Block ovulation

•Menopausal Hormone Therapy (MHT):

• Secondary effects of decreased

hormones … hot flashes, bone loss,

vaginitis atropicans, …

•Estrogen/Progestin – dependent

cancers: antagonism of ER and PR

•Abortifacients: induction of uterine

contractions

• Other uses

• Prostate ca:

•Estrogen block androgen production

•Chlorothianizan: palliative tx

Posology

• Estradiol tab: 1, 2 mg

• Estradiol benzoat, valerate,

cipionate inj im slow release: 05

mg/ml; 10, 20, 40 mg/ml; 5 mg.ml

• Diethylstilbestrol: 0.1; 0.25; 0,5; 1;

5 mg

• Ethynil estradiol tab: 0.02-0.5 mg

• Chlorothianizen caps: 12, 25 mg

11

Estrogen dose

• Premenopausal syndrome:

– Conjugated estrogen: 0.3-1.25 mg/day

– Ethynil estradiol: 0.01-0.02 mg/day

– 21-25 days

– Can be + MPA (Medroxy progesterone

acetate) 10 mg/day at day 10-14 --- ↓

endometrium ca

– If estrogen KI: MPA inj. 150 mg/month

• Osteoporosis:

– Ethynil estradiol 15 ug/day

12

• Equivalency:

– 50 ug estradiol ~ 50 ug

ethynilestradiol ~ 80 ug mestranol ~

5 mg diethylstilbestrol ~ 5 mg

conjugated estrogen

• Drug of choice:

– Price

– Individual situation

– Po

13

Side effect

• Nausea, vomitus

• Anorexia, headache

• Pain and tenderness of mammae

• Oedem ---- high dose

14

OHCH3

OH

OHCH3

OH

OH

OHCH3

OH

OH

OHCH3

OH

OHCH3

OH

CH3

OH

OH

CH3

OH

O

Synthetic Estrogenic

Estradiol look-alikes ….. agonists

Synthetic Estrogenic

CH3

OH

RO

CHC CH2

CH2OH CH

3

CH3 OH

CH

CHOH

OH

CH3

CH3

OMe

MeO

Cl

OMe

Ethinyl-estradiol R = H Diethylstilbestrol

Mestranol R = CH3

Chlorotrianisene Dienestrol

Diethyl-Stilbestrols (DES)

ANTI ESTROGEN

17

Estrogen Antagonists

OMe

MeO

Cl

OMe

Cl

OCH2CH

2N(CH

2CH

3)2

ClOCH

2CH

2N(CH

2CH

3)2

OCH2CH

2N(CH

2CH

3)2

CH3

R

Enclomiphene Zuclomiphene Tamoxiphen R = H4-Hydroxy tamoxiphen R = OH

Chlorotrianisene

(estrogenic)

Triphenylethylene Derivatives – Inverse Agonists

Selective Estrogen Receptor Modulators (SERM)

– Tissue specific activity …. Estrogenic for bone growth; anti-

estrogenic for uterine endometrial

growth

N

SOH

O

O

OH

OH

N

O

N

O

Cl

CH3

CH3

Raloxifene Nafoxidine Toremifene

– Single Receptor Single Response …. May not be valid!

Anti estrogen

• Inhibit estrogen work

– Progestin, androgen

• Inhibit estrogen synthesis/

competitive antagonist at the

estrogen receptor

– Clomifen, tamoxifen

20

Clomifen

• Rat:

– Weak estrogenic

– Moderate anti estrogenic

• Inhibit secretion of gonadotropin in

hypophyse

• Strong contraception for animal

• Tx for infertility: promote ovulation

– Amenorhoea, Stein-leventhal

syndrome, abnormal uterine

bleeding

– Dose: 50-75 mg/day, 2-3 weeks

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• Absorption

– Po: good,

– 50% is excreted via urine 5 days post intake

– Block negative feedback of estrogen to

adenohypophysis --- ↑ secretion of estrogen ----

cyst or ovarium enlargement in clomifen tx

• Posology: Tab clomifen sitrate 50 mg

• Uses:

– Infertility:

• Dose: 25-200 mg/day

• 5-10 days, start from 5th day of menstruation

• Clomifen works if HPA axis works, and estrogen endogen

enough

• Usually after 3x cycles of tx: pregnancy + in 75% women

– Palliative tx in ca mammae

• Se: ovarium enlargement, ovarial cyst, hot

flushes, GI tr effect, vission distb, gemelly,

headache

• KI: pregnancy

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Tamoxifen • Anti estrogen effect

– Competitive inhibitor in estrogen receptor

– Decrease number of receptor

• Pharmacokinetic

– Po: absorption good

– Metabolism: liver

– Main metabolite: N-desmetil-tamoxifen

– Excretion: faeces, little in urin

– SE: hot flushes, nausea, vomitus, per vaginal

bleeding, hypersecretion and pruritus in vulvae

• Uses:

– Palliative tx in breast ca post menopause

• Posology:

– Tab 10 mg

• Dose: 20-40 mg/day, 2 dd

23

PROGESTINE

24

Progesterone types

• Natural progesterone

– Synthesis: ovarium, luteal corpus,

adrenal cortex, testis, placenta

– Modification of testosterone, without

C19 atom

– Production:

• Foliculer phase: 1-5 mg

• Luteal phase: 10-20 mg

• End of pregnancy: hundreds mg

• Men: 1-5 mg/day

• Synthetic progesterone

(progestine derivative) 25

Derivatize ring D

Typical Progesterone Agonists

CH3

CH3

CH3

O

O

OCO(CH2)4CH

3

17a-hydroxy progesterone

caproate

CH3

CH3

CH3

O

O

OCOCH3

CH3

Medroxyprogesterone acetate

CH3

CH3

CH3

O

O

OCOCH3

CH3Megestrol

acetate

CH3

CH3

CH3

O

O

OCOCH3

Cl

Chlormadinone

acetate

CH3

O

CH3

CH3

O

Progesterone

Derivatize rings A & D

Testosterone Derivatives

Unusual Progesterone Agonists

CH3

CH3

OH

O

CH

Ethisterone

CH3

CH3

OH

O

CCH3

CH3

Dimethisterone

CH3

OH

O

CH

H

Norethisterone

CH3

OH

O

CH

H

Norethindrone

OCOCH3

N

CH

CH3

OH

H

Norgestimate

OH

O

CH

CH3

H

Norgestrel

19-Nor-testosterone Derivatives

Pharmacology • Luteal phase of endometrium

• Decrease secretion of secret in

endocervical gland

• Make the secret thicker

• In pregnancy: ↑↑↑ (prevent uterus

contractility)

• Pharmacokinetic

– Progesteron

• In oil ---- well absorbed

• Po ---- well absorbed, esp. synthetic

– Divided dose is better than single

dose 28

• Uses:

– Contraception • Combined with estrogen

• MPA, noretindron enantate ---- long term

contraception

– Dysfunctional uterine bleeding

• MPA 10 mg/day, 10 days

• Noethindron oral 5-10 mg/day, 5 days/month,

day 20-25th of menstrual cycle

– Endometriosis: norethindrone, danazol

– Abortus habitualis, imminens: ??

– Endometrial Ca: MPA 200-400 mg/day

oral, or 400-1000 mg im/week

• Posology

– MPA (tab 2, 5, 10 mg, depot 50 mg/ml),

norethindron (tab 5 mg)

29

PROGESTERONE

ANTAGONIST

30

Progesterone Antagonist

CH3

O

OH

CCH3

N

CH3

CH3

CH3

O

OH

CH2CH

2CH

2OH

N

CH3

CH3

Mifepristone

(RU-486)

(not the ‘morning-after pill’)

Onapristone

HORMONAL

CONTRACEPTION

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Review: the menstrual cycle

• Pulsatile GnRH (hypothalamus)

• LH and FSH (anterior pituitary) – LH stimulates:

• Ovulation (36 hrs after LH surge)

– FSH stimulates:

• Folliculogenesis

• Estradiol production

• Estradiol and progesterone (ovaries)

– Estradiol:

• Initial negative feedback on hypothalamus and pituitary

• Endometrial proliferation

• When high enough long enough, switches to positive feedback resulting in LH secretion

– Progesterone:

• Elevation indicative of ovulation

• “Pro-pregnancy”

• Inhibits LH & FSH

How does hormonal contraception

work?

• Estrogen: – Prevent estrogen surge --- prevents LH

surge → no ovulation

– Suppression of gonadotropin secretion during follicular phase, preventing follicular maturation and preventing ovarian hormone production

• Progesterone: – Creates thick cervical mucus to prevent

sperm penetration

– Impairs normal tubal motility and peristalsis

35

Combined mode of action of

estrogen and progestin • Prevents ovulation

• Thickens mucous in cervix

• Thins endometrium

Contraception

• Po, inj, intra vaginal, intra uterine,

condom, tubectomi, vasectomi

• topical: spermicid

• Implantasi subcutan, patch

36

Oral contraception

• Combination, sequential, mini pill,

morning after pill

• Primary Use

– Prevent pregnancy

• Secondary Uses

– Heavy or irregular menstruation

– Endometriosis

– polycystic ovary syndrome

– dysfunctional uterine bleeding

37

38

History of Oral Contraceptives

• 1937- discovery of effects of progesterone on ovulation

• 1940’s- Russell Marker isolates progesterone from Mexican yams

• 1951- Luis Miramontes synthesizes 1st progestin

• 1960- FDA approves “the pill”

• 1963- 1st oral contraceptive put on drug market

• 1965- number one form of birth control

• Late 1970’s- FDA mandated warning that indicated oral contraceptives carried risks of cancer and blood clots

39

Brands of Oral Contraceptives

• Alesse

• Brevicon

• Cyclessa

• Demulen

• Desogen

• Estrostep

• Genora

• Intercon

• Jenest

• Levlen

• Levlite

• Levora

• Loestrin

• Lo/Ovral

• Mircette

• ModiCo

• Necon

• N.E.E.

• Nelova

• Nordette

• Norethin

• Norinyl

• Ortho-Cept

• Ortho-Cyclen

• Ortho-Novum

• Ortho Tri-Cyclen

• Ovcon

• Ovral

• Tri-Levlen

• Tri-Noriny

• Triphasil

• Trivora

• Zovia

Oral contraception options

• Combined oral contraceptives (COC)

– (Mestranol)→ethinyl estradiol

• Estrogen level has decreased from 100 mcg/day → as low

as 20 mcg/day

• Most women should get no more than 35 mcg/day ethinyl

estradiol

• 50 mcg estrogen may be appropriate if:

– Spotting, absence of bleeding, or dysfunctional uterine

bleeding; Acne; Ovarian cysts; Endometriosis; Drug

interactions (induction of Cytochrome P450)

– Progestins

• Most potent: desogestrel, levonorgestrel, norgestrel

• Least potent: norethindrone

• Most androgenic: norgestrel > norethindrone & ethynodiol

• Least androgenic: desogestrel & norgestimate → may ↓ risk

of MI

» Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter

2006; 22 (8):220809.

• Monophasic vs. biphasic vs. triphasic – Biphasic and triphasic thought to more closely mimic

fluctuations in estrogen and progesterone levels during the menstrual cycle; ↓ dose-dependent adverse effects of progestin

– Recent Cochrane reviews conclude that choice of progestin is more important than phasic formulation

• Progestin-only pills (POP) – Women who are breastfeeding-can be started immediately

postpartum

– Considered safer in women w/ migraines, hx of thromboembolic disease, poorly controlled HTN w/ vascular disease or >35 yrs, diabetes w/ vascular disease or >35 yrs, SLE w/ vascular disease, hypertriglyceridemia, smoker over 35 yrs of age, CAD, CHF, cerebrovascular disease

» .

• Low-dose Monophasic Pills – Alesse, Levlite: low estrogen/progestin/androgen

– Loestrin 1/20, Fe 1/20: low estrogen, high progestin, medium androgen

– Nordette, Low Ogestrel: low estrogen, medium progestin, medium/high androgen

– Loestrin Fe 1.5/30: low estrogen, high progestin, high androgen

– Ortho-Cept: low estrogen, high progestin, low androgen

– Yasmin: low estrogen, progestin unclear, anti-androgenic and anti-mineralcorticoid

– Demulen 1/35: medium estrogen, high progestin, low androgen

– Ortho-Cyclen, Ovcon-35, Modicon: medium estrogen, low progestin, low androgen

– Ortho-Novum 1/50, Ortho-Novum 1/35: medium estrogen, medium progestin, medium androgen

• High-dose Monophasic Pills

– Ovcon-50: high estrogen, medium progestin, medium androgen

– Ogestrel 0.5/50: high estrogen, high progestin, high androgen

– Demulen 1/50: high estrogen, high progestin, medium/high androgen

» Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22 (8):220809.

• Biphasic Pills

– Mircette: low estrogen, high

progestin, low androgen

– Ortho-Novum 10/11: high estrogen,

medium progestin, low/medium

androgen

» Hormonal contraception. Pharmacist’s Letter/Prescriber’s

Letter 2006; 22 (8):220809.

• Triphasic Pills – Estrostep Fe: low estrogen, high progestin,

medium androgen

– Ortho Tri-Cyclen Lo: low estrogen, low progestin, low androgen

– Cyclessa: low estrogen, high progestin, low androgen

– Triphasil: medium estrogen, low progestin, low/medium androgen

– Ortho Tri-Cyclen: medium estrogen, low progestin, low androgen

– Tri-Norinyl, Ortho-Novum 7/7/7: medium estrogen, medium progestin, low/medium androgen

• Progestin-only Pills (“Mini-pill”)

– Micronor, Nor-QD: low progestin

• Emergency Contraception

– Plan B: high progestin x 2 pills (levonorgestrel 0.75 mg each)

– Women presenting w/in 72 hrs of unprotected intercourse or contraceptive failure (89% effective), consider for up to 5 days following unprotected intercourse

» Hormonal contraception. Pharmacist’s Letter/Prescriber’s

Letter 2006; 22 (8):220809.

47

Side Effects of Oral

Contraceptives • Changes in:

– Weight

– Sexual desire

– Vaginal discharge

– Menstrual flow

– Breast size

– Blood pressure

– complexion

• Other Common side effects: – Breakthrough bleeding

– Nausea headaches

– Urinary tract infection

– Depression

– Gum inflammation

48

Future of Oral Contraceptives

• Researchers continually trying to minimize

adverse side effects of oral contraceptives

• Pharmaceutical companies have to compete

with latest forms of contraception – Contraceptive vaccines

– Vaginal rings

– Intrauterine Contraception

– Cervical caps

– Transdermal patch

– Implants and injectables

Effect of contraception

• Reproductive organ

– Ovarium: ↓ function (reversible)

– Uterus: histological changes

myometrium hypertrophy, oedem

– Phalopian tube: ↓ function (reversible)

– Cervix: secret changes

– Mammarian gland: enlarge mamm

gland, estrogen prevents lactation

– Menstrual cycle: disturbance

– Other effects: liver function,

metabolism carbohydrate, fat,

protein

49

Side Effects

Too much ESTROGEN Nausea, bloating, breast

tenderness, ↑ BP, melasma,

headache

Too little ESTROGEN Early/mid-cycle breakthrough

bleeding, ↑ spotting,

hypomenorrhea

Too much PROGESTIN Breast tenderness, headache,

fatigue, changes in mood

Too little PROGESTIN Late breakthrough bleeding

Too much ANDROGEN ↑ appetite, wt gain, acne, oily skin,

hirsutism, ↓ libido, breast

tenderness, ↑ LDL, ↓ HDL

Hormonal contraception. Pharmacist’s Letter/Prescriber’s Letter 2006; 22

(8):220809.

Other benefits (lowered risk or

incidence):

• Dysmenorrhea

• Iron deficiency anemia

• Ectopic pregnancy (COC pill only)

• Ovarian cysts (higher dose estrogen pills only)

• Ovarian cancer

• Endometrial cancer

• Increased bone density

• Acne – Ortho Tri-Cyclen and Estrostep FDA-labeled for

treatment of acne*

Absolute Contraindications

• Known pregnancy

• Breast or uterine cancer

• Thromboembolic event or stroke

• Hepatitis

• Severe hypertension

• Thrombophlebitis

• Hyperlipidemia

• Anemia haemolytic chronic

• Ca mammae or genital, severe

mental deppression

53