50

Estrogen, progestins, and hormonal

contraceptives

50.1 ESTROGENS – TYPES AND MECHANISM OF ACTION

Produced mainly by Ovaries, placenta

Also produced by adrenals,

Small amounts testes, and peripheral
aromatization of androgens

By aromatization of androgens
Produced by granulosa
derived from thecal cells in the
cells
initial part of menstrual cycle

Major estrogens Estradiol, estrone, and estriol

Estradiol (most potent) Is converted in liver Estrone, estriol

Estrogen types

Natural estrogens Chemical alterations Synthetic estrogens

Nonsteroidal compounds Diethyl stilbesterol,

with estrogenic activity dinestrol

Natural estrogens Estradiol, estrone, estriol

Ethinyl estradiol

Synthetic estrogens Stilbestrol (oral)

Dienestrol (topical)

Bind to specific estrogen Regulate protein

Estrogens Enters nucleus Response
receptor synthesis

Mechanism of action
Uterus, vagina, ovary,
ERα breast, hypothalamus,
Types and location of blood vessels
estrogen ERα and ERβ
receptors (ER)
ERβ Prostate, ovaries

449
450 Pharmacology mind maps for medical students and allied health professionals

50.2 ACTIONS AND PHARMACOKINETICS

i. Growth and development of sex

of organs in females

ii. Stimulates development of

secondary sex characteristics

iii. Responsible for proliferative

phase of endometrium

iv. Promotes rhythmic

contractions of fallopian tubes
and myometrium

v. Makes cervical secretion thin,

watery and alkaline, and
facilitates entry of sperms

vi. Growth of ducts and stroma in

breast

Actions

vii. Inhibits activity of osteoclasts ↓ Bone resorption

viii. ↑ HDL and ↓ LDL

ix. Na+ and water retention

By ↑ clotting factors (II, VII,

x. ↑ Blood coagulability
IX and X) and ↓ antithrombin III

xi. Negative feedback control

on anterior pituitary

xii. Stimulates progesterone

receptor synthesis

Due to high first pass

Natural estrogens Are not effective orally Hence have a short t½
metabolism

Are orally effective and

Synthetic estrogens

Long-acting

Undergo glucoronide and sulfate

conjugation
Pharmacokinetics

Excreted in urine and bile

Undergo deconjugation by
intestinal bacterial flora

They are reabsorbed, resulting Hence ↑ duration

in enterohepatic circulation of action
 Estrogen, progestins, and hormonal contraceptives 451

50.3 USES, ADRs, AND PREPARATIONS

Cessation of normal Lead to menopause and its associated

ovarian function manifestations
Like hot flashes, sleep disturbances,
Vasomotor symptoms
genital atrophy, osteoporosis (fractures)
Night sweats, depression,
irritability

Incidence of CV disease

↓ Menopausal
Short-term HRT
1. Postemenopausal hormone symptoms
replacement therapy Reduces osteoporosis,
Long-term HRT
atherosclerosis and Alzheimer disease
2. Oral contraceptive
Progestin (medroxyprogesterone Added for the last Reduces endometrial and
or norethisterome) 12–14 days of each month breast cancer

Estrogen alone Is used in hysterectomised women

Oral conjugated estrogens (sulfate

esters) are most effective
Transdermal patch has fewer
systemic side effects
Anovulatory cycles
∴
are painless
3. Dysmenorrhea
Estrogens with progestions
Uses suppresses ovulation
Turner syndrome and
hypopituitarism
Estrogens develop secondary sex
characteristics
4. Delayed puberty in girls
Reduces chances of osteoporosis

Cyclic treatment is given

Topical estrogens ↓
5. Senile vaginitis
dyspareunia and urethral syndrome

Palliative treatment

Fosfeterol, a prodrug, is
6. Prostate carcinoma concentrated in prostate, activated
to stilbestrol
Venous thromboembolism GnRH agonists are preferred

Uterine bleeding

Breast cancer/tenderness

Gallstones (cholestasis)

Liver diseases

Mood changes
ADRs
Endometrial cancer

Migraine headaches

Gynecomastia and feminization In men

Edema and weight gain Due to Na and H2O retention

When given to pregnant woman

Teratogenicity ↑ Incidence of vaginal and

cervical cancer in female child
Conjugated estrogens (premarin) Genital abnormalities in
oral tablets, vaginal cream, injections male child

Transdermal patch
Preparations
Has estrogenic, progestogenic and
Vaginal cream/pessaries
weak androgenic activity

Tibolone No endometrial proliferation

Used continuously without cyclic

progesterone
452 Pharmacology mind maps for medical students and allied health professionals

50.4 ANTIESTROGENS

Compete with natural

estrogens for receptors
in target organs
They include
androgens and
clomiphene citrate Inhibit ovarian function
at anterior pituitary
Androgens
Oppose actions of
estrogens on target
organs

Antiestrogens Nonsteroidal Infertility due to

antiestrogenic anovulation
compound

Uses In vitro fertilization

↑ Sperm count
Male infertility and
testosterone secretion
Induces ovulation
Stimulates
Blocks both ERα and ERβ Blocks negative
Mechanism gonadotropin
Clomiphene citrate – (pure antagonist) feedback of estrogens
secretion (FSH and LH) Also ↑ sperm
50 mg OD from second count in men
day of menstrual cycle
for 5 days
Dose
Not to used for 6 cycles
due to risk of
ovarian cancer

Hot flushes,
hyperstimulation
syndrome, multiple
pregnancy,
ovarian cyst/malignancy
ADRs
Weight gain, breast
discomfort
 Estrogen, progestins, and hormonal contraceptives 453

50.5 SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) AND ESTROGEN

SYNTHESIS INHIBITORS

Act as an agonist,
antagonist or partial
agonist depending on site

Bone, lipid metabolism,

Agonist
brain, liver

e.g., Tamoxifen, raloxifene

Breast, pituitary,
Antagonist
endometrium

Genitourinary epithelium,
Antiresorptive effect
Partial agonist bone remodeling, Bone
(inhibit osteoclasts)
cholesterol metabolism

↓ LDL levels,
Estrogenic Lipid
reduces CV risk

Endometrium Causes proliferation

Actions

Breast cancer cells Reduces tumor size

Antiestrogenic

Periphery – Hot flushes

Tamoxifen

As palliation in advanced Both pre- and post-

Breast cancer (ER+ve)
cases menopausal women
Selective estrogen
receptor modulators
(SERMs) Hot flushes, vaginal
Uses
dryness

↑ Risk of
ADRs
endometrial cancer and

Thromboembolism

Antiresorptive hence
Bone reduces risk of vertebral
fractures

Estrogenic Lipid ↓ LDL cholesterol

↑ Risk of
Blood
thromboembolism

Antiproliferative on ER+ve
Breast
breast tumors

Antiestrogenic
Raloxifene Actions
Endometrium No proliferation

Continuous administration
of GnRH agonist inhibits
estrogen synthesis Prevention and treatment
Uses
of osteoporosis

Inhibits aromatase an
Aminoglutethimide enzyme essential for
estrogen synthesis Hot flushes, ↑ risk
Estrogen synthesis of thromboembolism
inhibitors
e.g., Anastrozole, ADRs
Selective aromatase
letrozole block production
inhibitors
of estrogens Does not ↑ risk of
endometrial cancer

Used in treatment of
breast cancer
454 Pharmacology mind maps for medical students and allied health professionals

50.6 PROGESTINS – TYPES, ACTIONS, AND PHARMACOKINETICS

Is secreted by ovary in second half

of menstrual cycle and

Placenta during pregnancy

Natural progesterone
Also synthesized by testis and
adrenals

Acts as precursor of various

steroid hormones

Natural Progesterone
Types

Medroxy progesterone acetate,

megestrol, hydroxyl progesterone
acetate
Synthetic progesterone
derivatives
Norethidrone
Synthetic 19-nortestosterone
(norethisterone),
derivatives
Norgestrel, Levonorgestrel

Newer progestins (with no

Gestodene, Norgestimate
androgenic activity)

Progestin means favors

i. Maintains pregnancy
pregnancy

ii. Secretory phase of endometrium

iii. Negative feedback on

hypothalamus and anterior
pituitary

iv. ↓ Tubal motility

and uterine contractions

v. Cervical mucus becomes scanty,

thick, viscous, and acidic, hence
Progestins
hostile to sperm penetration

vi. Proliferation of acini in

↓ Glucose tolerance
breast
Actions

vii. Metabolic ↑ LDL levels

viii. Sodium and water Stimulates lipase activity

retention hence fat deposition

ix. ↑ Body
temperature

x. Slight induction of
hypnosis

xi. ↓ Synthesis of
estrogen receptors

xii. Stimulate respiratory

center ( high dose)

Hence high dose oral

Pharmacokinetics High first-pass metabolism Hence not effective orally micronized progesterone
preparations are available
 Estrogen, progestins, and hormonal contraceptives 455

50.7 USES AND ADRs OF PROGESTINS

As combined pill With estrogen

Minipill
1. Contraception

Injectable (depot preparations)

Available as

Implants

Intrauterine contraceptive
Adjuvants with estrogens
devices (IUCD)
2. HRT in postmenopausal women
Prevents endometrial
Long-term therapy proliferation/carcinoma because
of estrogen therapy

Norethisterone or norethynodrel

Initial high dose arrests bleeding

3. Dysfunctional uterine
Later maintainance dose for 20 days
bleeding (DUB)

After 2–5 days of stopping

Withdrawal bleeding occurs
therapy

Treatment cycle continued for

Uses 3–6 months

Progestins alone or combination pills

Started 5 days before expected

period
4. Postponement of periods
Continued until required time as
needed

72 h after stopping
Withdrawal bleeding occurs
therapy

Dysmenorrhea, menorrhagia,
infertility, and dyspareunia

Continuous long-term oral

5. Endometriosis
progestins

Regresses lesions by causing

anovulation

Better than chemotherapy in

advanced stages

6. Endometrial carcinoma Oral progestins daily

IM medroxy progesterone
acetate weekly

Acne, irregular menses, depression,

breast tenderness, fluid retention, Androgenic actions
weight gain, hirsutism

↑ Risk of thromboembolism

ADRs
Older progestins ↑ lipid
Thus ↑ CV risk
levels

Newer progestins little or no

CV risk
456 Pharmacology mind maps for medical students and allied health professionals

50.8 ANTIPROGESTINS

∴ Competitive antagonist
of progesterone
receptors at
target organs

Has luteolytic property

When given during Hence decidual

Blocks progesterone
early pregnancy breakdown,
receptors in uterus
causes abortion detaches blastocyst

Mechanism of
This ↑
Mechanism of action termination of
prostaglandin levels
pregnancy

HCG ( human choronic

Hence uterine
gonadatropins) and
contractions occur
progesterone levels fall

It prevents midcycle This softens cervix and

Administered during
surge of gonadotropins causes expulsion
follicular phase
and delays ovulation of blastocyst

Also binds to
Early pregnancy up to
glucocorticoid
9 wks
receptors

Single oral dose

of 600 mg
i. Termination
of pregnancy
48 h later give
prostaglandins

Antiprogestins Mifepristone This ↑ uterine

contractions and helps in
expulsion of blastocyst

When given within

Prevents implantation
72 h after coitus
ii. Postcoital
Uses
contraception
Causes sloughing and Hence brings
shedding of decidua about abortion
iii. Monthly
contraceptive or
“morning after pill”

iv. Induction of labor in

case of intrauterine
fetal death

v. For cervical ripening

before abortion or
induction of labor

Uterine bleeding,
ADRs teratogenicity abdominal
pain, nausea, vomiting
 Estrogen, progestins, and hormonal contraceptives 457

50.9 DRUG TREATMENT OF MENOPAUSAL SYMPTOMS

Hormone replacement
Caused due to ↓
therapy
synthesis of estrogens
with estrogen

Hot flushes, sweating,

Reduces menopausal
anxiety, fatigue, vaginitis,
Manifestations symptoms
dryness, musculoskeletal
pain

Osteoporosis, urogenital ↓ Osteoporosis

atropy, dyspareunia, and CV risk
Long–term effects ↑ Risk of uterine
psychological disturbances fibroids and endometrial
and ↑ CV risk carcinoma
Drug treatment of Estrogen alone HRT
menopausal Menopause Hormonal Hence combination of
symptoms estrogen + progestin
reduces this risk

Orally, transdermally or
Administered
subcutaneous implants

Given continuously if
withdrawal
bleeding is undesirable Synthetic steroid with
effects like estrogen
Treatment – hormonal/ and progesterone
nonhormonal Tibolone
Reduces menopausal
symptoms

Clonidine α adrenergic agonists

Proponalol Non-selective β blockers

Nonhormonal agents

Dopamine antagonist

Veralipride
↓ Hot flushes and
palpitation
458 Pharmacology mind maps for medical students and allied health professionals

50.10 TYPES OF HORMONAL CONTRACEPTIVES

Mini pill

Single preparations
(progestin-only pill)

Emergency (postcoital) pill

1. Oral Monophasic

Biphasic

Combined estrogen and

progestin preparation

Triphasic
Most effective
contraceptive methods

Emergency (postcoital) pill

Greatly contribute
Hormonal contraceptives
to population control

Depot medroxyprogesterone
Implants: Norplant
acetate (DMPA)
Types
2. Parenteral

NET-EN (norethindrone
Injections (IM, SC)
enanthate)

Once a month
medroxyprogesterone
25 mg + estradiol
cypionate 5 mg

Progestasert

Intrauterine device (IUD)

Levonorgestrel (LNG)

3. Devices Transvaginal ring

Transdermal patch
 Estrogen, progestins, and hormonal contraceptives 459

50.11 COMBINED ESTROGEN (E) AND PROGESTIN (P) PREPARATIONS

Widely used, most

effective

Estrogen used Ethinyl estradiol (EE)

Norethisterone,
Progestin used levonorgestrel,
desogestrel, gestodene

Fixed amount if E and

Monophasic Efficacy 98%–99.9%
P in each pill

E is constant

Biphasic Day 1–10 EE (35 mcg) + N (0.5)

P varies according to
menstrual phase
Monophasic, biphasic, or
Day 11–21 EE (35 mcg) + N (1.0)
triphasic
E dose is slightly more
during midcycle
1. Combined estrogen (E)
E content ranges from
and progestin (P)
20–50 mcg
preparations P dose successively
↑ in 3
phases of menstrual cycle
P content ranges from
0.75–1.0 mg
EE (35 mcg) +
Triphasic Day 1–7
Noret (0.5 mg)

EE (40 mcg) +
Low-dose pills E is less than 35 mcg Day 8–14
Noret (0.75 mg)

Desogestrel, gestodene, EE (35 mcg) +

Day 15–24
norgestimate Noret (1.0 mg)

They ↑ HDL
∴
Newer progestins Lipid–friendly and ↓
atherogenic risk

Schedule for use

Menstrual cycle

Day 1 Day 21 Day 28

1 tablet orally for Pill-free/iron

Withdrawal bleeding
21 consecutive days iron/placebo
460 Pharmacology mind maps for medical students and allied health professionals

50.12 BENEFITS OF HORMONAL CONTRACEPTION AND CONTRAINDICATIONS

Avoids unwanted
pregnancy

↓ Menstrual blood
loss, anemia

↓ Dysmenorrhea,
premenstrual tension
Benefits of hormonal
contraception
↓ Pelvic inflammatory
disease

↓ Ovarian and endometrial

carcinoma

↓ Ovarian cyst and

benign breast tumors

Venous thromboembolism

Hypertension, cardiac
disease

Diabetes mellitus

Chronic liver diseases,

gallstones

Contraindications Epilepsy

Genital tract malignancy

Breast cancer

Migraine

Thyroid disease
 Estrogen, progestins, and hormonal contraceptives 461

50.13 SINGLE PREPARATIONS AND POSTCOITAL (EMERGENCY CONTRACEPTION)

PILL

Progestin only pill

(mini pill)

Very low dose of P

Safe in lactation and

women >35 yrs
Single preparations
1 tablet orally daily
Schedule
without a break

Efficacy 96%

Menstrual irregularities,
ADR
ectopic pregnancy

Morning-after pill

Oral P alone or with EE If taken within 72 h of

effective unprotected intercourse

Following rape

Unprotected intercourse

Use
Accidental condom
rupture during coitus
Postcoital (emergency
contraception) pill Mifepristone
(antiprogestin)
also is effective

Contraindication Confirmed pregnancy

ADR Nausea, vomiting E dose is high Use antiemetics

∴

Postcoital pill acts by

preventing implantation

If postcoital pill fails, LNG (0.75 mg)

pregnancy should be one pill
terminated (as OCPs are i. 2 one pill doses
teratogenic) 12 h
(within 72 h)

IUD within 5 days of LNG (0.75 mg)

coitus can also prevent one pill
implantation and
pregnancy
LNG (0.25 mg) +
EE (0.05 mg) 2 pills
ii. 2 two pill doses 12 h
Schedules of use (within 72 h)
LNG (0.25 mg) +
EE (0.05 mg) 2 pills
iii. Mifepristone 600 mg
single dose
Selective progesterone
receptor modulators
(SPRM)
iv. Ulipristal
30 mg single dose within
12 h or 5 days after
unprotected coitus
462 Pharmacology mind maps for medical students and allied health professionals

50.14 PARENTERAL CONTRACEPTIVES

150 mg IM once in
DMPA
3 months

Dose 30% less; once in

Injectables Subcutaneous DMPA
3 months

200 mg IM once in
NET-EN
2 months

Better patient compliance

∴
it avoids regular oral
medicines

Safe during lactation

Benefits
Reduced endometrial
On long-term use
carcinoma

Reduced dysmenorrhea,
menorrhagia

Menstrual irregularities

2. Parenteral
contraceptives
Mood changes, weight gain

Drawbacks Osteoporosis

↑ LDL, ↓ HDL

Delayed (6–8 months)

return of fertility on
stopping pills

Norplant

6 flexible rods containing

Subdermal implant
216 mg LNG

Contraceptive effects lasts

for 5 yrs
Implants
Immediate return of
fertility on removal of pill

Pain, irritation, infection at

ADRs site, headache, mood
changes, weight gain, acne

Single rod of 68 mg
Implanon desogestrel is effective for
3 yrs
 Estrogen, progestins, and hormonal contraceptives 463

50.15 DEVICES AND MECHANISM OF ACTION OF CONTRACEPTIVES

“T” shaped, inserted in uterine

IUD LNG device
cavity, effect lasts for 5 yrs

Low efficacy, has to be

Progestasert IUD contains progesterone
replaced yearly

Combination of EE and
desogestrel

Transvaginal ring
3. Devices
Effect lasts for a month

Contains EE and norgestimate

Applied over buttocks, upper

outer arm, lower abdomen,
etc.
Transdermal patch

Applied weekly for 3 wks

Then 1 week patch free Then withdrawal bleeding

Negative feedback on
→ Inhibits FSH and LH release Prevents ovulation
hypothalamus of E and P

Hence ovarian follicle

E suppresses FSH
fails to develop

P inhibits E-induced midcycle

LH surge

Mechanism of action
P makes cervical mucus thick
and unfavorable for sperm
penetration

Makes endometrium
unfavorable for implantation

Causes incordinated Hence transport of ovum,

contraction of cervix, uterus, sperm, fertilization,
and fallopian tubes implantation affected
464 Pharmacology mind maps for medical students and allied health professionals

50.16 ADVERSE EFFECTS, DRUG-INTERACTIONS, AND CENTCHROMAN

Dose-related

Current low-dose preparations have

minimal side effects i.e., Desogestrel, gestodene, and
norgestimate
Newer progestins
Are lipid friendly Hence reduces CV risk

Migraine headache

Nausea, vomiting

Edema
Adverse effects

Mild Weight gain

Breast tenderness

Amenorrhea

Irregular cycles

Venous thromboembolism

↑ Risk of MI

↑ Blood coagulability

Severe Hypertension

↑ Risk of breast, cervical, endometrial cancers

Cholestatic jaundice, gallstones

Impaired glucose tolerance

∴ Use alternative forms

Drug interactions

Enzyme inducers (rifampicin, phenytoin) ↓ Efficacy Hence can lead to contraceptive failure
of contraception

E is conjugated in liver Excreted via bile into gut Deconjugated by intestinal bacterial flora

Antibiotics which are incompletely absorbed

Destroy deconjugating bacteria Hence ↓ absorption of OCPs Hence contraceptive failure
from gut (ampicillin, tetracyclines)

Chroman synthetic nonsteroidal contraceptive

Developed by CDRI, Lucknow

Antiestrogenic and antiprogestogenic

Acts by preventing implantations

Onset quick i.e., < than 60 min

Duration if action – 7 days 30 mg twice weekly for 3 months

Then once weekly until contraception

Dosage
is desired
Tablet should be continued without
stopping during menses
Centchroman

Return of fertility Within 6 months of stopping drug

Efficacy 97%–99%

Devoid of side effects of hormonal

contraceptives

Benefits Well tolerated

No teratogenecity, carcinogenecity,
mutagenicity

Once-daily dosage, hence better compliance

ADRs Prolongation of menstrual cycles (10%)

Ovarian enlargement

Polycystic ovaries

Contraindications Hepato-renal dysfunction

Tuberculosis

Lactation