pharmacology notes for pharmacy student about natural and synthetic estrogens, progestins and androgens

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Dalia K. Zaafar
Lecturer of Pharmacology

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Female sex hormones
• In females, the ovaries and adrenal glands are
the main producers of sex hormones.
• Female sex hormones include estrogen,
progesterone, and small quantities of
testosterone.
Sex hormones

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Regulation of menstrual cycle
Sex hormones

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Pharmacological action of Estrogens
• Required for normal sexual
maturation & growth of female
• Stimulate development of vagina,
uterus & uterine tubes as well as
secondary sex characteristics
• Stimulate stromal development &
ductal growth in breast
• Responsible for accelerated growth
phase
Estrogens

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Pharmacological action of Estrogens
• Epiphysial closure of long bones at
puberty
• Distribution of body fat alteration to
produce typical female body shape
• ↓ rate of resorption of bone by
antagonizing effects of parathyroid
hormone
• stimulate adipose tissue production
Estrogens

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Pharmacological action of Estrogens
• ↑ in high density lipoproteins (HDL)
↓ in low-density lipoproteins (LDL)
• ↓ in total plasma cholesterol levels
• Plasma triglyceride levels are ↑
• ↓ Platelet adhesiveness
Estrogens

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Types of Estrogens
Estrogens
Estrogens
Natural Synthetic
Estradiol
Estrone
Estriol
Steroidal
Non-
steroidal
Ethinyl
estradiol
Diethylstilb
esterol

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Estrogen Receptors
• There are two types of Estrogen
receptors which are tissue specific
ERα and ERβ
• ERα is found endometrium, breast,
hypothalamus and blood vessels
• ERβ is found in prostate gland in,
ovaries, brain and heart cells
Estrogens

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I-Selective Estrogen Receptor Modulators
(SERMs)
• They are drugs with tissue selective
actions
• Estrogenic action in some tissue and
non estrogenic action in some other
tissue
• mixed agonists/antagonists
• Examples: Clomiphene, Tamoxifen
and Raloxifene
Anti-estrogens

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Selective Estrogen Receptor Modulators
(SERMs)
Anti-estrogens

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Clomiphene
• Binds to both ERα & ERß & acts as a
pure estrogen antagonist in all
human tissues
• Induces Gn secretion in women by
blocking estrogenic feedback
inhibition of pituitary gland
• Consequently, ovaries enlarge &
ovulation occurs
• Used in ttt of infertility due to
ovulation failure
Anti-estrogens

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Tamoxifen
• Binds to both ERα & ERβ
• acts as an estrogen agonist on bone
and lipid metabolism
• Act as a partial agonist on
endometrium
• Act as an antagonist on breast cells
and so can be used in treatment of
advanced breast cancer in
postmenopausal patients
Anti-estrogens

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Tamoxifen
Anti-estrogens

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Raloxifene
• Binds to both ERα & ERβ
• acts as a estrogen agonist in bone
and lipid metabolism
• Antagonist on endometrium and
breast
• Used in post menopausal
osteoporosis
Anti-estrogens

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II- Aromatase Inhibitors
• Anastrozole
• Selective inhibitor of aromatase
enzyme
• Decrease estrogen synthesis
• Used in treatment of breast cancer
in post menopausal patients
resistant to tamoxifen
Anti-estrogens

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Progesterone
• A natural steroidal hormone
• Precursor to estrogens, androgens &
adrenocortical steroids
• Secreted by the corpus luteum and
the placenta
Progesterone

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Progesterone
• Rapidly absorbed following
administration by any route
• Half-life in plasma 5 minutes
• Completely metabolized by liver
ineffective when administered orally
• High-dose oral micronized
progesterone preparations have
been developed that provide
adequate effect
Progesterone

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Synthetic progestin
• A number of synthetic progestin
with high oral activity has been
produced.
norethisterone, levonorgestrel,
norgestrel, desogestrel
Progesterone

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Uses of Progesterone
• Hormone replacement therapy &
hormonal contraception
• Dysmenorrhea
endometriosis & bleeding disorders
Progesterone

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Anti-progestin (Mifepristone)
• binds strongly to progesterone
receptor & inhibits activity of
progesterone
• Major use terminate early
pregnancies
• used in treatment of endometriosis,
breast cancer & other neoplasms
that contain glucocorticoid or
progesterone receptors
Progesterone

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Hormonal Contraceptives
• Hormonal preparations used for
reversible suppression of fertility
receptor & inhibits activity of
estrogen and progesterone
• They can be used in improvement of
menstrual cycle regularity, decrease
risk of endometriosis and
management of perimenopause
Contraceptives

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Oral contraceptive pills (Combined pills)
• Monophasic pills
Each tablet contain a fixed
concentration of both estrogen and
progestin
• Biphasic pills
Each tablet contain a fixed amount of
estrogen and but the amount of
progestin increases in the second half
of the cycle
Contraceptives

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Oral contraceptive pills (Combined pills)
• Triphasic pills
Introduced to permit reduction in
total steroid dose without
compromising efficacy
• mimic normal hormonal pattern in a
menstrual cycle
• Estrogen dose is constant (or varied
slightly) while amount of progestin
is low in first phase & is
progressively higher in second &
third phases
Contraceptives

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Oral contraceptive pills (Combined pills)
• Combined pills are taken for 21
consecutive days followed by 7 pill
free days causing a withdrawal
bleed
Contraceptives

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Oral contraceptive pills (Combined pills)
• MOA: Estrogen inhibits secretion of
FSH by -ve feedback……. Suppress
the development of ovarian follicle
• Progestin inhibits secretion of LH……
Prevent ovulation
• Both estrogen and progestin alter
the endometrium in a way to
discourage implantation
Contraceptives

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Oral contraceptive pills (Combined pills)
• Common adverse effects
• Weight gain (due to fluid retention
or anabolic effect)
• Nausea, depression, dizziness and
irritability
• Acne or increased pigmentation
• Thromboembolism and
hypertension
Contraceptives

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Oral contraceptive pills (Combined pills)
• Contraindications
• Thromboembolic& cerebrovascular
disease
• Moderate-to-severe hypertension
and hyperlipidemia
• Active liver disease
• Suspected malignancy of genitals/
breast
• Impending major surgery—to avoid
excess risk of postoperative
thromboembolism
Contraceptives

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Oral contraceptive pills (progestin only
pills)
• Progestins used: levonorgestrel,
norethisterone.
• Taken daily without interruption
• Less reliable than combined pills
• Used when estrogen is
contraindicated
Contraceptives

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Pharmacokinetics
• Ora contraceptives are metabolized
by hepatic cytochrome p450 system
• So any concomitant use of enzyme
inducers may lead to contraceptive
failure
• Examples of these drugs:
Carbamazepine, phenytoin,
Griseofulvin and rifampicin
Contraceptives

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Injectable contraceptives
• Depot medroxyprogesterone
acetate (DMPA) 150 mg at 3-month
intervals
• Norethindrone (Norethisterone)
enanthate (NEE) 200 mg at 2-month
intervals
• Highly effective
• Given i.m as oily solution
Contraceptives

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Injectable contraceptives
• Major limitations
• Menstrual irregularities, excessive
bleeding or amenorrhea are very
common
• Return of fertility may take 6–30
months after discontinuation
• May cause permanent sterility
Contraceptives

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Testosterone
• It is the male sex hormone which is
responsible of the normal
development in males at puberty
and to maintain fertility and libido
• Produced by testes, adrenal gland
and ovary
Androgens

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Testosterone
• Pharmacological action
• Skeletal muscle growth stimulation
• Acceleration of bone epiphysis
closure
• Stimulation of renal erythropoietin
Androgens

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Testosterone
• Uses
• Hypogonadism
• Anemia
• Osteoporosis
Androgens

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Testosterone
• Pharmacokinetics
• Due to extensive hepatic
metabolism it is taken transdermally
or i.m.
• Methyltestosterone is resistant to
hepatic metabolism so can be taken
orally
Androgens

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Danazol
• A synthetic steroid with
antigonadotrophic and anti-
estrogenic activities and some
androgenic properties
• used in the treatment of
endometriosis and some benign
breast disorders
• Voice changes, hirsutism and acne
are the main side effects
Androgens

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Types of anti-androgens
• 1- Androgen receptor antagonist
• Cyproterone acetate: active orally,
with increased risk of liver toxicity
and thromboembolic disease
Anti-androgens

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Types of anti-androgens
• 2- GnRH agonist
• GnRH agonists initially increase FSh
and LH secretion “Flare effect”.
After 2 weeks of administration a
profound hypogonadal effect is
achieved through receptor down
regulation
Anti-androgens

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Types of anti-androgens
• 2- GnRH agonist
A- Goserelin: used for breast cancer
B- Leuprolide: used for breast and
prostate cancer
C- Buserelin: used for prostate cancer
and male baldness
Anti-androgens

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Types of anti-androgens
• 3- Androgen synthesis inhibitor
A- Finasteride
• Used for hirsutism, male pattern
baldness and benign prostatic
hyperplasia
• Taken orally
• Inhibit the 5-α reductase II enzyme
So inhibit the conversion of
testosterone into DHT
Anti-androgens

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Types of anti-androgens
• 3- Androgen synthesis inhibitor
B- Ketoconazole
• At high dosages it inhibits the
conversion of cholesterol to
testosterone and glucocorticoids
• it can be used as a second-line
treatment for advanced prostate
cancer and in the treatment of
Cushing’s syndrome
Anti-androgens

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