Pharmacology Of Est

rogens
Presenters
Abubakar Jalloh
Matilda Sheriff
Pauline Dike
Outline of Presentation
Introduction to estrogen
Estrogen synthesis
estrogen receptors
Mechanism of action of Estrogens
Therapeutic uses of estrogens
Antiestrogens and their adverse effects
Drug interactions
CONTRAINDICATIONS
ESTROGEN
Biologically important natural estrogens
include estradiol, estrone, and estriol
Estradiol-17 is the most potent estrogen that is found
naturally in women.
Estrone is one-tenth as biologically
active as estradiol, and estriol is the weakest of the
three.
The ovary is the major site of estrogen and progestin biosynthesis
in nonpregnant premenopausal women.
In pregnant women, the fetoplacental unit is the majorsource of
estrogens and progestins.
Peripheral sites of estrogen synthesis include the liver, kidney,
brain, adipose tissue, skeletal muscle, and testes.

The combined estrogen and progestin production

by all of these peripheral sites amounts to 10% or less
of ovarian synthesis in normal premenopausal women.

In postmenopausal women, ovarian steroid synthesis

declines and peripheral estrogen biosynthesis accounts
for all estrogen produced, both in postmenopausal
women and in males
 The naturally occurring estrogens and progestins
are not orally active because they are rapidly
metabolically inactivated.

The major site of estrogen metabolism is the liver. It

is highly subject to first pass metabolism
Metabolites are also formed in GIT,Brain,Skin,and
other steroid target tissues.

A small fraction of estrogen enter the bile

 ESTROGENS
1. Estradiol – known also as 17β – estradiol
– Most patent estrogen produced and secreted by the ovary
– Principle estrogen in premenopausal women

2. Estrone – metabolite of estradiol that has approximately

1/3 the estrogenic potency of Estradiol
– Primary circulating estrogen after menopause
– Generated mainly from conversion of Androsteredione in peripheral
tissues

3. Estriol – metabolite of estradiol, is significantly less potent

than estradiol
– Present in significant amounts during pregnancy, because its principal
estrogen produced by placenta
 Estrogens
4. Ethynyl Estradiol ( Synthetic Steroid )
– Undergo less 1st – pass metabolism than naturally occurring
steroids
– Effective when administered orally at lower doses– Readily
absorbed when taken orally
• – Absorbed in the small intestine
• – Excreted with the bile
• 5. Conjugated Estrogens
– reduce symptoms of menopause ( hot flushes and vaginal dryness )
ESTROGEN SYNTHESIS
 Mechanism of Action
• After dissociation from their binding sites on sex
hormone –
binding globulin or albumin in the plasma, steroid
hormones
diffuse across the cell membrane and bind with high
affinity
to specific – receptor proteins
 Mechanism of Action
• 2 estrogen – receptor subtypes mediate the effects of the
hormone :
1. α receptor – considered as the classic Estrogen Receptor
2. β receptor – highly homologous to the α receptor
– α receptor
o N - terminal portion of receptor contains a region that
Promotes
transcription activation
– β receptor
o contains a Repressor Domain
Mechanism of Action
• Affinity for the receptor type varies with the particular
estrogen

• The α and β estrogen receptor isoforms vary in:

– Structure
– Chromosomal location
– Tissue distribution
Mechanism of Action
• Activated Steroid – Receptor Complex interacts with
nuclear chromatin to initiate Hormone – Specific RNA
synthesis :
– Attachment of 2 estrogen – linked receptors (estrogen
receptor dimer ) to the genome is required for a response
• This results in synthesis of specific proteins that mediate
a number of physiologic functions
• Steroid hormones are tissue and receptor specific :
– They may elicit the synthesis of different RNA species in
diverse
target tissues
 Mechanism of Action

• Activation of an estrogen receptor in the

membranes of hypothalamic cells has been
shown
to couple to a G – protein, thereby initiating
a 2nd – messenger cascade
Therapeutic uses
1. Contraception
2. Post – menopausal hormone therapy, called Estrogen –
Progesterone therapy ( EPT )
– It’s prescribed at the lowest effective dose for the shortest possible
time to relieve vasomotor symptoms and vaginal therapy
3. Osteoporosis
– Alendronate should be considered 1st – line therapy
4. Replacement therapy
– In Premenopausal patients in deficient in estrogen
– This deficient may be due to premature menopause because of lack
of development of ovaries
Therapeutic uses
5. Post – menopausal hormone therapy
– Primary indication for estrogen therapy is Menopausal Symptoms
1. Vasomotor instability – Hot flushes
2. Vaginal atrophy
6. For women who have not undergone a hysterectomy
– Combination of Estrogen with Progestin in Estrogen Therapy
decrease the risk of Endometrial Carcinoma associated with
unopposed estrogen
7. For women whose uterus has surgically removed
– Unopposed estrogen therapy is recommended
8. Primary Hypogonadism
– In combination with Progestins is stimulating development of
secondary sex characteristics in young women (11 – 13 years of age
)
Pharmacokinetics
• Naturally occurring estrogens
1. Readily absorbed though:
• GI tract
• Mucous membranes
• Skin
2. Taken orally
3. Estradiol
• Rapidly metabolized and partially inactivated by liver
4. Micronized Estradiol
• Has better bioavailability
• Although there’s 1st – pass metabolism, it’s not sufficient to
lessen the effectiveness when taken Orally
Pharmacokinetics
• Synthetic Estrogen Analogs
• Compounds such as Estradiol and Mestranol
1. Well absorbed through mucous membranes and skin
2. Oral Administration
• Mestranol quickly demethylated to Ethinyl Estradiol, which is
metabolized more slowly than naturally occurring estrogens
by Liver and Peripheral Tissues
– Being fat soluble, they are stored in adipose tissue from which
they
are slowly released
– Synthetic Estrogen Analogs have prolonged action and higher
potency compared to natural ones
Metabolism
• Estrogens are transported in the blood while bound to serum
albumin or sex hormone – binding globulin
• Bioavailability of estrogen taken orally is low due to 1st – pass
metabolism in liver
• To decreased the 1st – pass metabolism, the drugs may be
administered by :
1. Transdermal patch
2. Intravaginally
3. Inection
4. Topical gel or emulsion
• They are hydroxylated in the liver to derivatives that are
subsequently Glucuronidated or Sulfated.
• Parent drugs and their metabolites undergo excretion into the bile
and then reabsorbed through the enterohepatic circulation
• Inactive products are excreted via urine
Adverse Effects
• Most common of estrogen therapy
1. Nausea
2. Breast tenderness
• Post menopausal uterine bleeding may occur
• There is increased risk of :
1. TE events
2. Myocardial infarction
3. Breast cancer
4. Endometrial cancer
• Other effects
1. Headache
2. Peripheral edema
3. Hypertension
Selective Estrogen – Receptor Modulators SERMs
• Interact at estrogen receptors
• They display Selective Agonism or Antagonism
according to issue type
– For example :
• Tamoxifen is an estrogen antagonist in breast cancer
tissue, but can cause endometrial hyperplasia by
acting as partial agonist in the uterus
Selective Estrogen – Receptor Modulators SERMs
1. Tamoxifen ( 1st generation SERMs )
– Competes with estrogen for binding to the estrogen receptor in
breast tissue
– Currently used in the palliative treatment of metastatic breast
cancer in postmenopausal women
– May also be used as adjuvant therapy following mastectomy or
radiation and to decrease risk of breast cancer in high risk
patients
• Adverse effects
1. Hot flashes
2. Nausea
3. Vaginal bleeding
4. Menstrual irregularities
5. Hyperplasia in endometrium
6. Malignancies in endometrium
Selective Estrogen – Receptor Modulators
SERMs
2. Raloxifene ( 2nd generation SERMs )
– Use is based on its ability to decrease bone resorption and
overall bone tumor
1. Bone density is increased
2. Vertebral fractures are decreased
– Has little to no effect on the endometrium
– Lowers total cholesterol and LDL in the serum
– No effect on HDL or TAG levels
– Currently used for treatment of osteoporosis in
postmenopausal women
– Reduce the incidence of invasive breast cancer in
postmenopausal women
Selective Estrogen – Receptor Modulators SERMs
• Raloxifene
– Pharmacokinetics
1. Readily abrorbed orally
2. Rapidly converted to Glucuronide Conjugates through 1st – pass
metabolism
3. More than 95% is bound to plasma proteins
4. Undergo enterohepatic cycling
5. Excreted through the bile into the feces
– Adverse effects
1. Hot flashes
2. Leg cramps
3. Increased risk of DVT
4. Increased risk of PE
5. Increased risk of retinal – vein thrombosis
6. Should be avoided in women who are or may become pregnant
7. Women with past history or active history of TE should avoid use of the drug
8. Coadministration with cholestyramine can decrease the absorbtion by 60%
 3. Toremifene
– Properties and side effects similar to those of
Tamoxifen
– Risk of endometrial hyperplasia and cancer are
lacking
– Restricted to postmenopausal women with
metastatic breast
cancer
3. Clomiphere
– Acting as Partial Estrogen Agonist
– Interfering with negative feedback of estrogens on hypothalamus
– It’s increasing the secretion of GnRH and gonadotropins, leading to
stimulation of ovulation
– Used to treat infertility associated with anovulatory cycles
– No effect on women with ovulatory dysfunction due to Pituitary or
Ovarian failure
• Adverse effects
1. Headache
2. Nausea
3. Vasomotor flushes
4. Visual disturbances
5. Ovarian enlargement0
CONTRAINDICATIONS
Estrogens are contraindicated in the following;
Breast or endometrial cancer or vaginal
bleeding of unknown origin
Pregnancy
Hepatic dysfunction or liver cancer
Preexisting cardiovascular disease
Oral contraceptives are
contraindicated in;
-Pregnancy

-Smokers over age 35

-Diabetics
Contraindications of
antiestrogens
Pregnancy

Endometrial Cancer
 Drug Interactions
Certain concomitantly administered drugs may
interfere with the effectiveness of the oral
contraceptives
or lead to an increased incidence of breakthrough
bleeding. These include rifampin, isoniazid, ampicillin,
neomycin, penicillin V, chloramphenicol,
sulfonamides,
nitrofurantoin, phenytoin, barbiturates, primidone,
analgesics, and phenothiazines
The oral contraceptives also may decrease the
effectiveness of anticoagulants, anticonvulsants,
tricyclic antidepressants, guanethidine, and
hypoglycemic agents.
The causes of such drug interactions include
alterations in hepatic microsomal drug-metabolizing
enzymes,
competition for binding sites on plasma proteins, and
enhanced excretion.
Aromatase inhibitor
s
Letrozole; The newest
 The duration of remission in breast
cancer patients treated with letrozole exceeds that of
tamoxifen, and the drug can be used even in tumors that
have developed resistance to tamoxifen.
Letrozole is
orally active and is excreted primarily in the urine. The
incidence of side effects is rare. It does not change
serum corticosteroid, aldosterone, or thyroid hormone
levels.
Anastrozole (Arimidex) is another promising
third-generation aromatase inhibitor.
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