2023 DUHS DMC 4th YEAR MBBS

REPRODUCTION MODULE-II
PHARMACOLOGY LECTURE

ESTROGENS AND ANTI-ESTROGENS

By
DR AFRINA RAZA
MBBS(MD),M.Phil
Professor(Assistant),Department of Pharmacology
DMC,DUHS
 OBJECTIVES AND REFERENCES
• ILOs:
1. Describe ESTROGENS. Estrogen Modifiers and SERMs
2. Discuss key indications, adverse effects and drug‐drug interactions
associated with these drugs
3. Describe examples, mechanism of action of drugs included in ANTI-
ESTROGENS.
4. Discuss key indications, adverse effects and drug‐drug interactions
associated with these drugs
REFERENCES:
1.Katzung`s Pharmacology,15th Edition ,Chapter # 40
2.Google Websites.
 Overview: Endocrine Physiology
REVISION
Hypothalamus (GnRH)
& Pitutary

Luteinizing Hormone &

Follicle Stimulating Hormone

Ovaries & Testes

Reproduction
REVISION Synthesis of ESTROGEN
24 28
21 22
CH 3 CH 2 CH 2 CH 3
20
18 CH
Cholesterol 12 CH 3
17
CH 2
23
CH 2 25

11 CH 3
19 13 16
C D 27
1 CH 3 14
2 9 15
10 8
A B
3
7
5
OH 4 6

Pregnenolone

Progesterone
DHEA
Androstenedione
Androstenedione OH

Testosterone aromatase
OH

Estradiol
REVISION Physiology
Reproductive Tissues
Growth of
Vaginal Ovarian
Mammary
Epithelium follilcle Gland
Growth of
endometrium Sperm
transport

Lowers
LIPIDS Plasma cholesterol Decreases
rate of bone
ESTROGENS resorption BONES

PSYCHO Behavioral effects Reduces

Bowel motility GUT

Liver synthesis of BLOOD

LIVER/PROTEINS Transport Proteins Maintains normal
Increases blood coagulability SKIN
skin structure

Non-reproductive Tissues
 Regulation: Impact on Reproductive Tissues
REVISION Luteal
Follicular
Days
0 4 8 12 16 20 24 28 32

Plasma Level
Ovulation Progesterone
Estradiol

Basal Body
Temperature
oF

Vaginal
Cornification

Cervical
Mucus
Elasticity

Glycogen Vacuoles
Endometrium

Menses Menses
Proliferative Secretory
Phase Phase
REVISION Relationship of estrogen and progesterone
Synthetic Estrogens.
(Estrogen Modifiers,Therapeutic
Formulations and Uses= Therapeutic
Estrogens=HRTs)
HOW Eg
works
with its
receptor
at
TARGET
TISSUE
 WHEN DO WE NEED ESTROGENs? Therapeutic Estrogens
CLINICAL USES /INDICATIONS:
UN-MARRIED:
1. Primary Hypogonadism.
2. Suppress ovulation in patients with dysmenorrhea or
3. Suppress ovulation in patients of hirsutism due to excess
secretion of ovarian androgens
FERTILE AGE:
1. Infertility treatments
2. Oral Contraceptives
PRE- AND POST-MENOPAUSAL:
1. Pre- and Postmenopausal Hormonal Therapy(HRTs)
 Therapeutic Estrogens

DRUG COMMENTS

Estradiol Main estrogen used IN PREMENOPAUSAL women. Poor oral BA

Effective as a patch (ESTRADERM, ESTROGEL)
Intramuscular delivery sustains release for weeks (DEPO ESTRADIOL)

Topical administration with vaginal cream (ESTRING)

Ethinyl- Semi-synthetic: commonly used on ORAL CONTRACEPTIVES

estradiol
Estrone Natural estrogen.conjugated.(PREMARIN) to help reduce symptoms of
MENOPAUSE ;such as hot flashes, vaginal dryness
 USES : Effects
of HRTs` in
Post-
Menopausal
Females

Increased risk of MI
and stroke, especially
in the first year
 Therapeutic Estrogens
• ADVERSE EFFECTS:
• GENERALIZED:
• Nausea, fluid retention,
breakthrough bleeding,
change in menstrual flow,
breast tenderness.
• CVS RISKS:
• Thrombolytic complications,
Hypertension.;
• CANCER RISKS:
• Endometrial Carcinoma;
Breast Carcinoma.
• CONTRAINDICATIONS:
• GENERALIZED:
• Pregnancy, incomplete bone growth,
undiagnosed genital bleeding.
• CVS RISKS:
• Stroke, Thrombophlebitis, Or
Thromboembolic Disease., Heart
Disease.
• CANCER RISKS:
• Women with family history of breast
or uterine cancer (BRCA gene)
 Therapeutic Estrogens

DRUG INTERACTIONS:

• Estrogens  the effects of oxytocin on the uterus.

• St. John's wort may cause  OR loss of contraceptive or

hormonal-replacement efficacy of estrogens
 Uses: HRT - Formulations
FYI
Early HRT used estrogen alone: increased risk of uterine (endometrial) cancer. As
a result, addition of progestins is now used to limit endometrial hyperplasia
Medroxyprogesterone (MPA) acetate is most commonly used

• Various regimens are used: estrogen for 25 days with inclusion of MPA during
last 10-13 days of estrogen, 5-6 days with no hormones

• Combination formulations:
PREMPRO (PREMARIN plus MPA) given at fixed dose daily;
PREMPHASE (PREMARIN for 28 days and MPA for days 14-28)

• Newer combos of estrogens with progestins:

FEM HRT (estradiol plus norethindrone acetate)
ORTH PREFEST (estradiol plus norgestimate)

• Vaginal creams (PREMARIN) or a ring device (ESTRING) can be used

instead of oral doses . Reduces vaginal dryness, yeast infections and urinary
tract infections.
SERMs
(Selective Estrogen Receptor Modulators)
HOW Eg
works
with its
receptor
at
TARGET
TISSUE
 TAMOXIFEN:
• competitive, partial agonist; an INHIBITOR of ESTRADILOL at Eg-
Receptor at SOME sites.
• It is first selective SERM, having mixed properties of agonist/
antagonist but exact MOA is not known.

• MOA:
• Tamoxifen selectively binds to estrogen receptors in breast
tissue…In breast cancer patients…. it competitively binds to Eg-R
(inplace of Eg)….. differential activation of hetero-dimers (ER-
ALFA and ER-BETA….Eg-R changed shape………co-activators
CANNOT be stimulated…….inhibits breast cancer cells`
proliferation.
MOA OF SERMs:
 EFFECTS OF
SERMs:
Tamoxifen

2-3 fold increased

risk of DVT
WHY?
HOW?
 SERMs: Tamoxifen continued

USES:
Most effective in treatment of BREAST-tumors that are:
• ER-positive (50% response) or
• ER + PR positive (70-80% response rates).
• Responses of ER-negative tumors is < 10%.

• Adjuvant therapy with chemo or radiation in treatment.

• Preventative agent for women at high risk for breast cancer.

• Resistance is usually developed in 5 years, which may, in

part, reflect alterations in the ER receptors in the tumors.
 SERMs: Other
Raloxifene (EVISTA):
MOA:
High affinity for both ER- and ER-.Estrogenic on lipid
and bone but Does NOT cause proliferation of the
endometrium or breast tumor cells
USE:
Treatment of osteoporosis in post-menopausal women.

SIDE EFFECTS:
•  risk of Deep Vein Thrombosis and
• Pulmonary Embolism
Estrogen Synthesis Inhibitors
• EX:Clomiphene
•MOA:
•Older, partial agonist.

•Weak agonist and

strong antagonist for
ER- or ER- at
ant.pituitary.
•Competitive inhibitor
of endogenous
estrogen…amplitude
of the LH and FSH
pulses…increases
OVULATION chances.
 Anti-Estrogens

MAJOR USE:
Induction of ovulation in women with an intact
hypothalamic-pituitary-ovarian axis. Treatment of infertility.

ADVERSE EFFECTS:
• Multiple Births,
• Ovarian Cysts
 Estrogen Synthesis Inhibitors

Ex: Anastrozole

MOA:
Specifically block the local production of estrogens in hormonally-
responsive tissues by inhibiting AROMATASE

USE:
Second-line treatment for breast cancer in patients whom
tamoxifen therapy is unsuccessful, but new studies rapidly proving
its efficacy and promoting earlier use.
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