Estrogen, Anti estrogen,

Progestin and
Hormonal Contraseption
Dr. Rika Yuliwulandari, PhD

Female Sex Hormonal Steroids

Natural Estrogens
CH3 OH

CH3 O

CH3 OH
OH

HO

HO

Estradiol
Intramuscular (100%)

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

HO

Estrone
intramuscular (33%)

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

Natural Progestin

O
CH3
CH3

Progesterone

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

CH3

Estriol
oral (1.6%)
(?????)

Biosynthesis and Metabolism of Estradiol and Progesterone

H 3C
CH 3

H3C
CH3

CH3

CH3

HO

HO

cholesterol

CH3 OH

CH3

CH3

CH3

HO

CH3 OH

pregnenolone

testosterone

estradiol

H3C
CH3

progesterone

CH3 O

CH3

HO

O
CH3

OH

CH3

CH3

HO

CH3

OH

5b-metabolite

20a/b-hydroxy
metabolite

CH3

CH3 OH

CH3

CH3

estrone

H3C

H3C

OH

HO

O
OH

6a-hydroxy
metabolite

Conjugation to glucuronides, sulfates, etc.

estriol

Ovulation

ESTROGEN

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

 Other sources of estrogen:

Equus: pregnancy --- 100 mg/day
Ekuilin and ekuilenin

Estrogen like:
Flavon, isoflavon, chumesthan
derivate

 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
8
DNA damage

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

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

Synthetic Estrogenic
Estradiol look-alikes .. agonists
CH3 OH

H3C

CH3 OH

HO

HO

HO

CH3 OH

CH3 OH

HO

HO
OH

HO

HO

CH3 OH

CH3 OH

HO

Synthetic Estrogenic
Diethyl-Stilbestrols (DES)
CH3 OH
C

H 2C

CH

HO

RO

Ethinyl-estradiol R = H
Mestranol R = CH3

Cl

MeO

OH

CH2

Diethylstilbestrol

OMe

H 3C CH

HO

OMe
Chlorotrianisene

H 3C

CH3

C CH
3
H

Dienestrol

OH

ANTI ESTROGEN

17

Estrogen Antagonists
Triphenylethylene Derivatives Inverse Agonists
Cl

Cl

OCH2CH2 N(CH2CH3)2

CH3

OCH2CH2N(CH2CH3)2

OCH2CH2 N(CH2CH3)2

Tamoxiphen
R=H
4-Hydroxy tamoxiphen R = OH

Zuclomiphene

Enclomiphene

OMe

Cl

MeO

OMe

Chlorotrianisene
(estrogenic)

Selective Estrogen Receptor Modulators (SERM)

Single Receptor Single Response . May not be valid!

Tissue specific activity . Estrogenic for bone growth; antiestrogenic for uterine endometrial
growth
O

H3C

O
N
CH3

OH
HO

Raloxifene

Cl

HO

Nafoxidine

Toremifene

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

21

 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

22

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

Typical Progesterone Agonists

H3C

CH3

CH3

CH3
OCO(CH2)4CH3

CH3

CH3

Derivatize ring D

17a-hydroxy progesterone
caproate

Progesterone

Derivatize rings A & D

O
CH3

CH3

CH3

OCOCH3

Medroxyprogesterone acetate

Megestrol CH3
acetate

CH3
OCOCH3

CH3

O
CH3

CH3

OCOCH3

CH3

CH3

CH3

O
Cl

Chlormadinone
acetate

Unusual Progesterone Agonists

CH3 OH

CH3 OH

Testosterone Derivatives

CCH3

CH

CH3

CH3
O

CH3

Dimethisterone

Ethisterone

19-Nor-testosterone Derivatives

HO N

Norethisterone

Norethindrone

Norgestimate

OH
CH

CH

H3C

OCOCH3

CH

CH

H3C

CH3 OH

CH3 OH

Norgestrel

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
H3C

CH3

N
CH3 OH

Mifepristone
(RU-486)
(not the morning-after pill)

H3C

N
CH3 OH

CCH3

CH2CH2CH2OH

Onapristone

HORMONAL
CONTRACEPTION
32

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

Combined mode of action of

estrogen and progestin

Prevents ovulation
Thickens mucous in cervix
Thins endometrium

35

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

History of Oral Contraceptives

1937- discovery of effects of progesterone on
ovulation
1940s- 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 1970s- FDA mandated warning that
indicated oral contraceptives carried risks of
cancer and blood clots
38

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

39

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. Pharmacists Letter/Prescribers 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, antiandrogenic 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. Pharmacists Letter/Prescribers

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. Pharmacists Letter/Prescribers
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. Pharmacists Letter/Prescribers
Letter 2006; 22 (8):220809.

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
47

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

48

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,
49
protein

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. Pharmacists Letter/Prescribers 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