Pharmacology 2

Estrogens and
Androgens
Rufayda Manassrah
2024-2025
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Menstrual Cycle
Hypothalamic-pituitary-ovarian axis
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Sex Hormones Synthesis

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4
 Sex Hormones
• Sex hormones produced by gonads are necessary
for: conception, embryonic maturation,
development of primary and secondary sexual
characteristics at puberty.
• Therapeutic uses of gonadal hormones:
replacement therapy, for contraception,
management of menopausal symptoms.
• Antagonists effective in cancer chemotherapy.
• All gonadal hormones are synthesized from the
 precursor (cholesterol(
• Aromatization is the last step in estrogen synthesis. 5

the liver, adipose tissue,

Produced and secreted brain, skin, and heart,
mainly by the ovary Estrogens adrenal gland
Extragonadal organs:

• Estradiol: the most potent estrogen produced and

secreted by the ovary, the main estrogen in
premenopausal women.
• Estrone: metabolite of estradiol, has one-third the
potency of estradiol. Estrone is the primary estrogen
after menopause, generated mainly from conversion
of androstenedione in peripheral tissues.
• Estriol: metabolite of estradiol, less potent than is
estradiol, present in significant amounts during
pregnancy, the main estrogen produced by the
placenta.
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7

Preparations of conjugated Estrogens

Oral preparation used for hormone replacement
therapy:
• Naturally obtained:
⮚From urine of pregnant mares: sulfate esters of
 estrone and equilin.
⮚Plant-derived conjugated estrogen products. •
Synthetic estrogens: Ethinyl Estradiol (less
first-pass metabolism than, more effective
when administered orally at lower doses).
8

Preparations of conjugated Estrogens

• Selective Estrogen Receptor Modulators

(SERMs): Nonsteroidal compounds bind to
 estrogen receptors and exert either estrogenic
or antiestrogenic effects on target tissues • (e.g.,
tamoxifen and raloxifene)

Mechanism of action of Estrogens

• Estradiol workings by:
⮚Binding the estrogen receptor (ER): estrogen receptor alpha
 (ERα) and estrogen receptor beta (ERβ).
⮚It also exerts potent agonism of G Protein-coupled estrogen
receptor (GPER), which is recognized an important regulator
of this drug's rapid effects.
• Once the estrogen receptor has bound to its ligand, it
enters the nucleus of the target cell, regulating gene
transcription and formation of messenger RNA. This
mRNA makes contact with ribosomes producing specific
proteins that express the effect of estradiol upon the
target cell.
• Agonism of estrogen receptors increases pro-estrogenic
effects, leading to the relief of vasomotor and urogenital
symptoms of a postmenopausal or low estradiol state 10
Mechanism of action of
Estrogens Genomic effect
 Non-Genomic effect 11

Pharmacodynamics of
Estrogens
⮚Development of primary sex characteristics,
e.g., external genitalia, uterus, ovaries,
fallopian tubes, and regulation of the
menstrual cycle.
⮚Development of secondary sex
characteristics, e.g., fat distribution, breasts,
and pubic hair. ⮚Regulate body temperature.
 ⮚CNS: lipido and mood
⮚Estradiol exert favorable effects on bone
density by inhibiting bone resorption.
⮚Have beneficial effects on the plasma lipid
profile 12

Pharmacodynamics of Estrogens
⮚Estradiol acts on the on the estrogen receptors to
relieve vasomotor systems (hot flashes), urogenital
symptoms (vaginal dryness and dyspareunia).
 ⮚Estrogens cause an increase in hepatic synthesis of
various proteins, which include sex hormone binding
globulin (SHBG), and thyroid-binding globulin (TBG).
⮚Estrogens are known to suppress the formation of
follicle-stimulating hormone (FSH) in the anterior
pituitary gland.
⮚Estrogen-mediated dilation of coronary arteries
occurs by the increased formation and release of nitric
oxide and prostacyclin in endothelial cells.
13

Pharmacodynamics of Estrogens
• A note on hyper-coagulable state, affect
cardiovascular health, and blood pressure: – Estradiol
increase risk of cardiovascular disease, DVT, and stroke,
– should be avoided in patients at high risk of these
conditions.
– hyper-coagulable state in both estrogen-containing oral
contraceptive (OC) use and pregnancy.
⮚estrogen causes an increase in levels of plasma renin and
angiotensin. Estrogen-induced increases in angiotensin,
causing sodium retention, which is likely to be the
mechanism causing hypertension after OC treatment. 14
 Pharmacokinetics of Estrogens
Natural estrogens and their esterified or
conjugated derivatives
• Absorbed through the gastrointestinal tract,
skin, and mucous membranes.
• Taken orally, estradiol is rapidly metabolized
(partially inactivated) by the microsomal
enzymes of the liver.
• Micronized estradiol has better bioavailability
(less first-pass metabolism, does not lessen the
 effectiveness when taken orally)
15

Pharmacokinetics of Estrogens
Synthetic estrogen analogs:
• Ethinyl estradiol, mestranol, estradiol valerate
• Well absorbed after oral administration. •
Mestranol is quickly demethylated to ethinyl
estradiol
• Estradiol valerate is rapidly cleaved to estradiol and
valeric acid.
• Being fat soluble, stored in adipose tissue (slowly
 released).
• Metabolized more slowly than natural estrogens by
the liver and peripheral tissues.
• Have prolonged action and higher potency 16

Metabolism of Estrogens
Estrogens are transported in the blood bound to serum
albumin or sex hormone–binding globulin.
• Bioavailability of orally estrogen is low due to first pass
metabolism.
• To reduce first-pass metabolism, the drugs may be
administered by:
 – transdermal route (patch, topical gel, topical emulsion, or spray),
– intravaginally (tablet, cream, or ring),
– or by injection.
• They are hydroxylated in the liver to derivatives that are
subsequently glucuronidated or sulfated.
• The parent drugs and their metabolites excreted into bile
and are then reabsorbed through the enterohepatic
circulation.
• Inactive products are excreted in urine. 17
The Enterohepatic Circulation of
Estrogens
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 Menopause
• Menopause: loss of ovaries function and
cessation of menstruation, occurs in women
aged between 45 and 55 years (mean age 51
years.)
• Women are said to be postmenopausal when
menstruation has ceased for 6-12 months and
blood serum levels of FSH increased. •
Menopause symptoms:
⮚hot flushes, insomnia, declining bone mass, night
 sweats, mood disturbances and vaginal dryness. •
The treatment: Estrogen therapy
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Therapeutic uses of Estrogens

Estrogens are most frequently used for:
1. Contraception
2. Postmenopausal hormone therapy (HT) 3.
Prevention of osteoporosis (current guidelines
recommend use of other therapies, alendronate
over estrogen).
4. Replacement therapy in premenopausal patients
 who are deficient in this hormone.
– Estrogen deficiency due to: inadequate functioning of the
ovaries (hypogonadism), premature menopause, or
surgical menopause.
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Therapeutic uses of Estrogens

Postmenopausal HT:
• The primary indication is menopausal symptoms:
vasomotor instability (e.g. hot flashes/ flushes) and
vaginal atrophy.
• For women who have an intact uterus: –
 combination of estrogen plus progestogen (E+P) reduces
the risk of endometrial hyperplasia and carcinoma –
unopposed estrogen (daily use of estrogen without the
addition of progestogen).
• For women with hysterectomy, unopposed
estrogen therapy is recommended, progestins alter
the beneficial effects of estrogen on lipid
parameters.
21

Therapeutic uses of Estrogens

Postmenopausal HT:
• The amount of estrogen used in replacement therapy is
less than the doses used in oral contraception. • The
adverse effects are usually less.
• Transdermal patch or gel is effective.
• HT should be prescribed at the lowest effective dose
for the shortest time, due to increased risks of HT
(increased risk of cardiovascular events and breast
cancer)
• Women who only have urogenital symptoms, such as
vaginal atrophy, should be treated with vaginal rather
than systemic estrogen.
22

Benefits associated with

postmenopausal estrogen
replacement
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 Therapeutic uses of Estrogens
Contraception:
• The combination of an estrogen and
progestogen provides effective contraception
– Oral, transdermal, or vaginal route.
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Therapeutic uses of Estrogens

Other uses:
• Stimulate development of secondary sex
characteristics in young women with primary
 hypogonadism: estrogen therapy mimicking the
natural cyclic pattern, usually in combination
with progestogen. Continued treatment is
required after growth is completed.
• Premature menopause or premature ovarian
failure: estrogen and progestogen replacement
therapy is used
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Adverse Effects of Estrogen

The most common adverse effects of estrogen
therapy:
• Nausea
• Breast tenderness
• Increase risk of thromboembolic events,
myocardial infarction
• Increase risk of breast and endometrial cancer

• [Note: The increased risk of endometrial cancer

can be offset by including a progestogen along
with the estrogen therapy.]
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Adverse Effects of Estrogen 27
Selective Estrogen Receptor Modulators
(SERMs)
• SERMs are a class of estrogen-related
compounds that display selective agonism or
antagonism for estrogen receptors depending
on the tissue type.
• Tamoxifen,
• Toremifene,
• Raloxifene,
• Clomiphene, (estrogen receptor blocker in hypothalamus)
• Ospemifene.
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Mechanism of action of SERMs

• Tamoxifen, toremifene, raloxifene compete
with estrogen for binding to the estrogen
receptor in breast tissue. So regress and treat
some breast tumors
• Note: Normal breast growth is stimulated by
estrogens.
• Raloxifene in bone acts as estrogen agonist,
leading to decreased bone resorption,
increased bone density, and decreased
vertebral fractures.
• Tamoxifen, raloxifene does NOT have
significant estrogen receptor agonist activity in
the endometrium and, therefore, does NOT
predispose to endometrial cancer.
• Raloxifene lowers serum total cholesterol

and low
density lipoprotein (LDL). 29

Mechanism of action of SERMs

• Clomiphene acts as a partial estrogen agonist
and interferes with the negative feedback of
estrogens on the hypothalamus.
• This effect increases the secretion of
gonadotropin-releasing hormone and
gonadotropins, leading to stimulation of
ovulation.

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 Therapeutic uses of SERMs
• Tamoxifen: treatment of metastatic breast cancer, •
Tamoxifen: adjuvant therapy following mastectomy or
radiation for breast cancer.
• Tamoxifen, raloxifene: prophylactic therapy to reduce
the risk of breast cancer in high-risk patients. •
Raloxifene: prevention and treatment of osteoporosis
in postmenopausal women.
• Clomiphene: treatment of infertility associated with
anovulatory cycles.
• Ospemifene: treatment of dyspareunia (painful
sexual intercourse) related to menopause
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Pharmacokinetics of SERMs
• The SERMs rapidly absorbed after oral
administration.
• Tamoxifen is metabolized by cytochrome
P450
• Raloxifene is converted to conjugated form
through first-pass metabolism.
• These agents undergo enterohepatic cycling,
• Primary route of excretion is through the bile
into feces.
32

Adverse effects of SERMs

• Tamoxifen and toremifene → hot flashes,
nausea.
• Tamoxifen → endometrial hyperplasia and
malignancies
– This limit the length of time on the drug for some
 indications.
• Tamoxifen is metabolized by cytochrome P450 so
it subject to many drug interactions.
– CYP450 inhibitors prevent the formation of active
metabolites of tamoxifen and reduce the efficacy (e.g.,
amiodarone, haloperidol, risperidone).
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Adverse effects of SERMs

• Raloxifene → Hot flashes and leg cramps. •
Raloxifene → increase risk of DVT, pulmonary
embolism, and retinal vein thrombosis.
 – Women with history of venous thromboembolic events
should not take it.
– Cholestyramine reduce the absorption of raloxifene,
concurrent use should be avoided.
• Clomiphene (dose related) → headache, nausea,
vasomotor flushes, visual disturbances, ovarian
enlargement.
• Use of clomiphene increases the risk of multiple
births (twins or triplets).
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Aromatase Inhibitor (AIs)

• They blocks the activity of aromatase enzyme,
which lowers the amount of estrogen made by
the body
• Used to treat some types of breast cancer or
to keep it from coming back.
• Used to help prevent breast cancer in women
at a high risk.
• Examples of aromatase inhibitors are:
Anastrozole, Letrozole, Exemestane. 35
SERMs vs. AIs
36