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ESTROGENS:
Three ovarian estrogens form are secreted
1-Estradiol: is the major estrogen produced by the
ovary& the most potent
2-estriol: is the main form of hormone secreted
During pregnancy by the placenta.
3-Estrone: is the primary circulating Estrogen after
menopause.
The estrogenic potency of Estradiol is 12 times that
of estrone and 80 times that of estriol. the level of
estrogen in male 20–80 pg/ml while in female
1-30-49 pg/ml(early follicular).
2-150-449 pg/ml(mid-cycle).
3-101-209 pg/ml(luteal),
4-< 41 pg/ml(postmenopausal).

 the ovary is the major site of estrogen synthesis
in nonpregnant women. in pregnant women the
fetoplacental unit is the major site.
 Peripheral site of estrogen synthesis include liver,
kidney, adipose tissue& skeletal muscle &this
account for about 10% of total estrogen
production in premenopausal women. After
menopause estrogen synthesis decline greatly&
Peripheral production account for most estrogen
synthesis
 during the first part of the menstrual cycle
estrogens are produced in the ovarian follicle by
the theca interna and granulosa cells.
 After ovulation, the estrogens as well as
progesterone are synthesized by granulosa and
theca cells of the corpus luteum

Mechanisms of Action
 There are two form of estrogen receptor ERα & ERβ.
ERα found primarily in the uterus, kidneys, liver, and
heart,
ERβ is found primarily in the ovaries, prostate,
lungs, gastrointestinal tract, hemopoietic
system,and CNS.
 17-beta-estradiol binds equally well to both
receptors.
estrone bind preferentially to the alpha receptor.
estriol to the beta receptor.
 Estrogens circulate in the bloodstream bound to sex
hormone binding globulin(SHBG)or albumin

 Then estrogen diffuse through target cell
membrane. binding of estrogen to these
nuclear-receptor proteins which found in
cell form estrogen–receptor complex which
is then transported to the cell nucleus
where it interacts with deoxyribonucleic
acid (DNA) to produce ribonucleic acid
(RNA). These substances stimulate cell
reproduction and production of various
proteins that stimulate a number of
physiological function of estrogen.

Physiological action of the estrogen
1-Breast:Stimulate growth at puberty by causing
deposition of fat, formation of connective
tissue and construction of ducts.
2- Sexual Organs: Cause the endometrial lining
of the uterus to proliferate, Enlarge the uterus,
vagina, and external genitalia at puberty,
3-Anterior Pituitary Gland: Decrease pituitary
secretion of follicle-stimulating hormone.they
increase LH secretion (positive feedback) in
other circumstances,they inhibit LH secretion
(negative feedback).

4-Metabolism:
Increase protein anabolism, bone growth, and
epiphyseal closure in young person.
sodium and water retention
serum triglycerides, and high-density
lipoproteins (HDL).
low-density lipoproteins (LDL).
Increase the amount of cholesterol in bile
and thereby increase gallstone formation
5-Blood Coagulation: enhance coagulation by
increasing blood levels of several clotting
factors and increase platelet aggregation.

Route of administration of estrogen&progesterone
1-orally: ethinyl estradiol
2- Transdermal preparation: Estradiol transdermal
system which provides constant serum levels similar to
ovarian estradiol secretion
3- Cream : such as natural progesterone cream
4-Injection: medroxyprogesterone acetate
5- Vaginal ointment: Premarin ointment
6- Conjugated estrogen preparations: Premarin

 Estrogen has more than 90% protein binding
to(SHBG) or albumin which is biologically
inactive. so only the free form can enter cell &
therefore biologically active
 estrogens are deactivated in the liver, mainly by
cytochrome P450 3A4 enzymes.
 The estrogens then conjugated with glucuronic
acid or sulfuric acid, which makes them water
soluble and readily excreted through the
kidneys.
 Metabolites are also formed in the GIT tract,
brain, skin, and other steroid target tissues.
Most of the conjugates are excreted in urine;
some are excreted in bile.

they produce the same effects as endogenous
hormones. they divide into four group
1-Naturally occurring estrogens:(estradiol, estrone) they
given by injection because they are rapidly
metabolized if administered orally. Some crystalline
suspensions of estrogens and oil solutions of estrogens
prolong drug action by slowing absorption.
2-Conjugated estrogens eg: Premarin, which given
orally 0.3–1.25 mg daily for 21d in the therapy of
menopause complaint.
3-synthetic steroidal derivatives of natural estrogens
which include

1-Estradiol (ethinyl estradiol, Mestranol,polyestradiol
phosphate
2-Estrone (estrone sulfate)
3-Estriol(Promestriene)
4-Other synthetic derivatives such as, Equilenin, Equilin
some of these derivatives are effective with oral
administration.
ethinyl estradiol: it is The most widely used synthetic
steroidal estrogen& also consider the prototype for this
group
Uses:
1-Menopausal Symptoms:(0.02–0.05) mg orally
2- Female Hypogonadism: 0.05 mg orally by Sequential
therapy (one to three times daily for 2 wk with addition
of progestin for last 2 wk of month).

 is well absorbed with oral administration and reaches
peak plasma level within 2 hours.
 It is 98% bound to plasma proteins and its half-life
varies from 6 to 20 hours.
 Ethinyl estradiol undergoes extensive ﬁrst-pass
hepatic metabolism and is further metabolized and
conjugated in the liver the conjugates are then
excreted in bile and urine.
4-Nonsteroidal synthetic preparations: are usually
administered orally or topically. These include
dienestrol, benzestrol, hexestrol, methestrol,
methallenestril, and diethylstilbestrol.
They are chemically altered to slow their metabolism
in the liver. They are also less bound to serum proteins
than naturally occurring hormones.

1-replacement therapy in deficiency states. As in
hypofunction of the pituitary gland or the ovaries.
initiated with small doses of estrogen (0.3 mg
conjugated estrogens or 5-10 mcg ethinyl estradiol)
on days 1-21 each month and is slowly increased to
adult doses maintained until the age of menopause
(approximately 51 years).
2-Menopause:to relieve symptoms of estrogen
deficiency as atrophic vaginitis and vasomotor
instability, which produces hot flashes. When
estrogen is prescribed for women with a uterus, a
progestin added to prevent endometrial cancer
this called ERT or HRT.

3-osteoporosis:The amount of bone is maximal in
the young active adult in the third decade of life
and begins to decline more rapidly in middle age
in both men and women. Conjugated estrogens
(Premarin) PO 0.625 mg daily for 21 d,
4- component in birth control pills and other
contraceptive preparations. contraceptives act by
several mechanisms
A-they inhibit hypothalamic secretion of
gonadotropin-releasing hormone, which inhibits
pituitary secretion of FSH and LH.
B-the drugs produce cervical mucus that resists
penetration of spermatozoa into the upper
reproductive tract.

C- the drugs interfere with endometrial
maturation and reception of ova that are
released and fertilized.
An estrogen, when combined with a progestin
is used widely in the 12-45 year age group to
control fertility If pregnancy does occur,
estrogens are contraindicated because their
use during pregnancy has been associated
with the occurrence of vaginal cancer in
female offspring and possible harmful effects
on male offspring.

Adverse effects: estrogen excess cause widespread of effect
but the most prominent effect include:
1-Uterine bleeding: Estrogen therapy is a major cause of
postmenopausal uterine bleeding. also there is a risk
of thromboembplic formation.
2- Melasma: symmetrical hyperpigmented patches which
seen on the lateral aspect of the forehead, upper part
of the cheek, and mandibular area. This occur because
the hormones cause excessive production of melanin
and this corresponds to darkening of the skin

3-endometrial hyperplasia frequently develop in
premenopausal &postmenopausal women receiving
estrogen alone.
which regarded as premalignant condition & will
develop high rate of incidence of endometrial
carcinoma, this can be prevented by
administration of a progestational agent with
estrogen in each cycle
5- Nausea, weight gain and breast tenderness are
common and can be minimized by using the
smallest effective dose of estrogen
,Hyperpigmentation also occurs.
4- Estrogen therapy is associated with an increase
incidence of cholestasis, gallbladder disease, and
hypertension.

1- Estrogens should not be used in patients with
estrogen-dependent neoplasms such as carcinoma of
the endometrium.
2- Estrogens Contraindications in individualds who are at
high risk for carcinoma of the breast.
3- Estrogens should be avoided in patients with
undiagnosed genital bleeding, liver disease, or a
history of thromboembolic disorder.
4- the use of estrogens should be avoided by heavy
smokers.
5- Estrogens dose should be minimized in patients with
hypertension.

SERMs: are nonhormonal pharmacological agent that
bind to ERs. Characteristic feature of SERMs is that
a given agent will act as an estrogen agonist in one
or more tissue and as an estrogen antagonist in one
or more other estrogen target organ .Tamoxifen
,Raloxifene ,Clomiphene ,Toremifene, Afimoxifene,
Cyclofenil , Arzoxifene , are examples of
nonsteroidal SERMs.
Tamoxifen: competitive partial agonist inhibitor of
estradiol at the estrogen receptor
.

Uses:
1-it is partial agonist in breast& therefore used in
the palliative treatment of breast cancer in
postmenopausal women
2-approved for chemoprevention of breast cancer in
high-risk women.
Pharmacokinetic: It is a nonsteroidal agent that is
given orally. Tamoxifen half-life 7-14 h and is
predominantly excreted by the liver. It is used in
doses of 10-20 mg twice daily.
Adverse effect: :
1- nausea and vomiting occur in 25% of patients.
2-Tamoxifen is full agonist in endometrium
&prolonged use lead to a fourfold to fivefold
increase in the incidence of endometrial cancer.

Raloxifene:A new SERM partial estrogen agonist
Uses: use in treatment & prevention of postmenopausal
osteoporosis .Raloxifene is an estrogenic antagonist in both
breast& endometrial tissue. the estrogenlike properties of
raloxifene result in maintenance of lipid serum profile( LDL
with no change in either HDL or triglyceride),
Pharmacokinetic: Raloxifene is 95% bound to plasma protein
and it subject to a high first-pass effect, has a very large vd
and a long half-life (> 24 hours), so it can be taken once a
day. absorption of Raloxifene is impaired by cholestyramine.
Toremifene: A SERM drug with properties similar to that of
Tamoxifen it uses in treatment of Metastatic breast cancer in
postmenopausal women
Adverse effect: Hot ﬂashes, nausea, hypercalcemia,

Fulvestrant : 500mg imis a SERM .it is administered as monthly
injection. it used against advanced breast CA in
postmenopausal women.
Tamoxifen, Raloxifene, Clomiphene, are orally active. the
primary route of excretion of all three drugs in the feces.
the most common unwanted effect associated with these
drugs is
1-increased risk of thromboembolism
2-increase frequency of hot flashes
both effect are attributed to their estrogenic activity.
OTHER INHIBITORS :
Anastrozole: a selective nonsteroidal inhibitor of aromatase
(the enzyme required for estrogen synthesis) is effective
breast tumors have become resistant to tamoxife.

Letrozole : is similar Anastrozole
Exemestane: a steroid molecule, is an irreversible
inhibitor of aromatase. Like anastrazole and letrozole,
it is approved for use in women with advanced breast
cancer.
Fadrozole: is a newer oral nonsteroidal inhibitor of
aromatase activity. These compounds appear to be as
effective as tamoxifen.
Uses:
1-use in breast cancer.
2-aromatase inhibitors have employed as adjuncts to
androgen antagonists in the treatment of precocious
puberty and as primary treatment in the excessive
aromatase syndrome.

CLOMIPHENE:: Clomiphene a partial estrogen agonist,
kinetic: This compound is active when taken orally. About
half of the compound is excreted in the feces within 5 days
after administration.
Mechanism of action: Clomiphene has been shown to
effectively Cause an increase in the secretion of
gonadotropins and estrogens by blocking the feedback
inhibitory influence of estrogens on the hypothalamus,
causing a surge of gonadotropins, which leads to ovulation.
Clinical Use: used in the treatment of disorders of ovulation in
patients who wish to become pregnant. a single ovulation is
induced by single course of therapy, patient must be treated
repeatedly until pregnancy is achieved .

When clomiphene is administered in doses of 100 mg/d for 5
days,a rise in plasma LH and FSH is observed after several
days. In patients who ovulate, the initial rise is followed by
a second rise of gonadotropin levels just prior to ovulation.
Adverse effect:
1-ovarian enlargement: this consider is the most common
adverse effects. the degree of enlargement tends to be
greater and its incidence higher in patients who have
enlarged ovaries at the beginning of therapy
2- hot flushes which resemble those experienced by
menopausal patients. also reports of eye symptoms
due to intensification and prolongation of afterimages.
These are generally of short duration. Headache,
constipation, allergic skin reactions.

3-nausea and vomiting, increased nervous tension,
depression, breast soreness, weight gain, and heavy
menses have also been reported. The incidence of
multiple pregnancy is approximately 10%.
Clomiphene has not been shown to have an adverse
effect when inadvertently given to women who are
already pregnant.
Contraindications:
1-women with enlarged ovaries are thought to be more
sensitive to this drug and should receive small doses.
Maximum ovarian enlargement occurs after the 5-
day course has been completed, and many patients
can be shown to have a palpable increase in ovarian
size by the seventh to tenth days.

2- Treatment with clomiphene for more than a
year may be associated with an increased risk
for low-grade ovarian cancer.
3- Special precautions must also be taken in
patients who have visual symptoms associated
with clomiphene therapy, since these symptoms
may make activities such as driving more
hazardous.

 Progesterone is the most important progestin in humans.
 it serves as a precursor to the estrogens, androgens, and
adrenocortical steroids.
 It is synthesized in the ovary, testis, and adrenal from
circulating cholesterol. Large amounts are also
synthesized and released by the placenta during
pregnancy
 In the ovary, progesterone is produced primarily by the
corpus luteum. in pregnant woman Plasma levels of
progesterone are further elevated and reach their peak
levels in the third trimester of pregnancy.

 The corpus luteum produces progesterone during
the ﬁrst few weeks of gestation. Then the placenta
produce the progesterone needed to maintain the
endometrial lining of the uterus.
 Normal males progesterone plasma levels < 0.63
ng/ml. while in female
1- < 0.63 ng/ml (follicular)
2-> 4.7 ng/ml (mid-luteal)
3-< 0.63 ng/ml (postmenopausal).
 When fertilization does not take place, the
progesterone level decrease and menstruation
occurs.

Mechanism:
 There are two isoforms of progesterone receptor: α and
β.
 Progestins enter the cell and bind to progesterone
receptors that are distributed between the nucleus and
the cytoplasm.
 The ligand-receptor complex binds to a progesterone
response element (PRE) to activate gene transcription.
 The response element for progesterone appears to be
similar to the corticosteroid response element, and the
specificity of the response depends upon which receptor
is present in the cell as well as upon other cell-specific
receptor and interacting transcription factors.
 The progesterone-receptor complex then bind to DNA
which lead to production of various protein & growth
factor which responsible for physiological function of it.

1- progesterone continues the changes in the
endometrial lining of the uterus begun by estrogens
during the ﬁrst half of the menstrual cycle. These
changes provide for implantation and nourishment of
a fertilized ovum.
2- In addition to its effects on the uterus, progesterone
prepares the breasts for lactation by promoting
development of milk-producing cells.
3- Progesterone also may help maintain pregnancy by
decreasing uterine contractility.
4- Progesterone can compete with aldosterone for the
mineralocorticoid receptor of the renal tubule,
causing a decrease in Na+ reabsorption.

1-Progestins are most often used in combination with an
estrogen in contraceptive products.
2-They also are used to suppress ovarian function in
dysmenorrhea , endometriosis, and uterine bleeding.
3-Progestins also used in combination with estrogen for
long-term HRT in postmenopausal women with intact
uteri. the purpose of a progestin is to prevent
endometrial cancer, which can occur with unopposed
estrogenic stimulation.
4-Diagnostic uses: Progesterone can be used as a test of
estrogen secretion. The administration of progesterone
or medroxyprogesterone, 150 mg/d for 5-7 days, is
followed by withdrawal bleeding in amenorrheic
patients only when the endometrium has been
stimulated by estrogens.

1- Progesterone decrease high-density lipoprotein (HDL)
and increase low density lipoprotein (LDL) cholesterol,
both of which increase risks of cardiovascular disease.
2- progesterone increases insulin levels but does not
impair glucose tolerance, but long-term administration
of progestins may decrease glucose tolerance and make
diabetes mellitus more difficult to control.
3-combined progestin plus estrogen in replacement
therapy in postmenopausal women may increase breast
cancer risk significantly compared with the risk in
women taking estrogen alone.
4-progestational compounds alone and with combination
oral contraceptives may increase blood pressure in
some patients

Contraindications: progestational compounds are
commonly contraindicated in depression, preexisting
cardiovascular disease, breast CA, vaginal bleeding
of unknown cause.
Synthetic preparation of progestins
Synthetic preparation of progestins have the same
effect as endogenous progestins. Generally they
divided into two chemical classes
first chemical class of synthetic progestins is derived
from testosterone &is known as 19-
nortestosterone,these compound have some
androgenic activity.

There are three classes of these compound
1-1st class: Norethindrone , Norethindrone acetate,
Ethynodiol diacetate
2-2nd class: Levonorgestrel, Norgestrel, Norelgestromin
3-3rd class: Desogestrel ,Gestodene Norgestimate
These new group of synthetic progestins has ,been
introduced as components of oral contraceptives &
they have lower androgenic activity than older
synthetic progestins.

Second chemical class of synthetic progestins
characterized by addition of Alkyl chain to C17 position
which biological half-life of these compound and
increase there progestational activity,
an examples of these compound include
hydroxyprogesterone, medroxyprogesterone,
megestrol, dimethisterone, Chlormadinone, these
compound are the most closely related
pharmacologically as well as chemically to
progesterone. these compound metabolized in the
same manner as progesterone & excreted in urine.
Norethindrone considered the prototype of progestins
agonist it undergoes ﬁrst-pass metabolism so that it is
only 65% bioavailable. It reaches peak plasma levels in
0.5 to 4 hours and has a half-life of 5 to 14 hours. It is
metabolized by conjugation & hydroxylation in the
liver and excreted in urine and feces.

1-administration of progestational compounds alone or
with combination oral contraceptives indicate that the
progestin in these agents may increase blood pressure
in some patients.
2- The more androgenic progestins also reduce plasma
HDL levels in women & increase the level of plasma
LDL which increase liability to atherosclerosis.
3-nausea, vomiting ,weight gain & increase risk of
thromboembolic formation.
Contraindications: progestational compounds are commonly
contraindicated in pregnancy ,depression, preexisting
cardiovascular disease, breast CA, vaginal bleeding of
unknown cause.

Mifepristone: is progesterone antagonist that binds
strongly to the progesterone receptor and inhibits the
activity of progesterone.
 The drug has luteolytic properties in 80% of women when
given in the mid-luteal period.
 also because the compound has a long half-life, large
doses may prolong the follicular phase of the subsequent
cycle and so make it difficult to use continuously for this
purpose.
 the drug use as an emergency postcoital contraceptive,
though it may result in delayed ovulation in the
following cycle.
 the drug also binds to and acts as an antagonist at the
glucocorticoid receptor.

Therapeutic Use:
1-Mifepristone major use to terminate early pregnancies
(during first trimester). Doses of 400-600 mg/d for 4
days or 800 mg/d for 2 days successfully terminated
pregnancy in over 85% of the women.
2-it also useful in the treatment of endometriosis,
Cushing's syndrome, breast cancer, and possibly other
neoplasms such as meningiomas that contain
glucocorticoid or progesterone receptors.
Adverse effect:
1- prolonged bleeding that on most occasions did not
require treatment. As many as 5% of patients have
vaginal bleeding requiring intervention.
2-vomiting, diarrhea, and abdominal or pelvic pain.

Danazol: Danazol has weak progestational, androgenic,
and glucocorticoid activities. is used to suppress
ovarian function.
mechanism:
 Danazol inhibits the mid-cycle surge of LH and FSH
and can prevent the compensatory increase in LH and
FSH following castration, but it does not significantly
lower or suppress basal LH or FSH levels in normal
women.
 it does bind to sex hormone-binding globulin and
corticosteroid-binding globulin.

 it does not inhibit aromatase, the enzyme required
for estrogen synthesis. it increases the mean clearance
of progesterone, probably by competing with the
hormone for binding proteins, and may have similar
effects on other active steroid hormones.
Pharmacokinetic: Danazol is slowly metabolized, having
a half-life of over 15 hours. This results in stable
circulating levels when the drug is administered twice
daily. It is highly concentrated in the liver, adrenals,
and kidneys and is excreted in both feces and urine.
Ethisterone a major metabolite of danazol, has both
progestational and mild androgenic effects.

Therapeutic use:
1-Danazol used as an inhibitor of gonadal function
therefore use in the treatment of endometriosis. it
can be given in a dosage of 600 mg/d. The dosage is
reduced to 400 mg/d after 1 month and to 200 mg/d
in 2 months.
2-Danazol also used in the treatment of fibrocystic disease
of the breast and hematologic or allergic disorders,
including hemophilia, Christmas disease(Factor IX),
idiopathic thrombocytopenic purpura, and
angioneurotic(sudden accumulation of liquid under the
skin, similar to nettle rash edema).

Adverse effect:
1-weight gain, edema, decreased breast size,
2-increased hair growth, deepening of the voice,
headache.
3- changes in libido, and muscle cramps. Occasionally,
because of its inherent glucocorticoid activity, danazol
may cause adrenal suppression.
Contraindication:
1-Danazol should be used with great caution in patients
with hepatic dysfunction, because it produce mild to
moderate hepatocellular damage in some patients, as
evidenced by enzyme changes.
2-also contraindicated during pregnancy and breast
feeding, as it may produce urogenital abnormalities in
the offspring.

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