ESTROGEN
(Female
Sex hormones)
Natural estrogens- Estradiol is
the major estrogen secreted by the ovary.
It is
synthesized in the graafian follicle, corpus luteum and placenta from
cholesterol
Synthetic estrogens – Natural
estrogens are inactive orally and have a short duration of action due to rapid
etabolism in liver. Synthetic compounds have been produced:
Steroidal-
Ethinylestradiol, Mestranol, Tibolone.
Nonsteroidal-
Diethylstilbestrol (stilbestrol) Hexestrol, Dienestrol
Regulation of
secretion
Actions of
estrogen
Sex organs: Growth of
uterus, fallopian tube, and vagina
• Vaginal
epithelium – thickened, stratified, cornified
• Responsible
for the proliferation of endometrium in preovulatory phase
• Increase rhythmic
contraction of fallopian tube and uterus
• Induce
watery alkaline secretion from the cervix – favours sperm penetration
• Sensitizes
uterus to oxytocin
• Deficiency
of estrogen – atrophic changes
Secondary sex characters:
• Breast
growth
• Pubic
axillary hair
•
Accumulation of fat
• Feminine
body contours and behaviour are influenced
Metabolic effects – Anabolic
(weaker than testosterone)
• Promotes
fusion of epiphysis
• Maintains/
Prevents resorption and inhibition of osteoclast pit formation
• Expression
of bone matrix proteins
• Promotes
positive calcium balance
Other actions –
• Mild salt
water retention
• Combination
contraceptives – Impaired glucose tolerance
• Improved
lipid profile
• Stimulate
fibrinolytic activity
• Induce NO synthase
– promote vasodilation
• Increases
lithogenicity of bile and decrease bile salt secretion
Mechanism of action
• Estrogens
bind to specific nuclear receptors in target cells and produce effects by
regulating protein synthesis.
• Estrogen
receptors (ERs) present in female sex organs, breast, pituitary, liver, bone,
blood vessels, heart, CNS and in certain hormone responsive breast carcinoma
cells
• The ER is
analogous to other
steroid receptors: agonist
binding to the ligand
binding domain brings about receptor dimerization and interaction with
‘estrogen response elements’ (EREs) of target genes
• Gene
transcription is promoted
Pharmacokinetics
• Natural –
Inactive orally
• Bind to
Steroid Hormone Binding Protein (SHBG)
• Estradiol
gets converted to estrone in liver – estriol derived from estrone
• Glucuronide
and sulfate conjugation
• Excreted
urine and bile
•
Enterohepatic circulation
• Transdermal
estradiol: 5, 10 and 20 cm2 delivers 0.025, 0.05, 0.1 mg
ADR
• Males: Suppression
of libido, gynacomastia, feminisation
• Early
fusion of epiphyses in children
• Pregnant
women: Increase incidence of vaginal/
cervical carcinoma in female offspring
• Other
genital abnormalities in male and female offspring
• Post-menopausal
women: increased risk of irregular
bleeding and endometrial carcinoma
• Accelerate
the growth of existing breast cancer
Uses
• As
contraceptive
• In Hormone
Replacement Therapy
• Senile
vaginitis
• Delayed
puberty in girls
• Dysmenorrhoea
• Acne
• Dysfunctional
uterine bleeding
• Carcinoma
prostrate
• Hirsutism
ANTIESTROGEN
Clomiphene citrate
• Pure antagonist at estrogen receptor
• Inhibits estrogenic feedback – stimulates
ovulation
• Used in sterility (Amenorrhoea, anovular
cycles)
• ADR: Polycystic ovary, multiple pregnancy,
risk of ovarian tumour
• To aid in vitro fertilization
• In men – Spermatogenesis
Selective Estrogen Receptor Modulators (SERMs)
• Tamoxifen citrate: Potent estrogen antagonist in breast
carcinoma cells, blood vessels
• Partial agonist at uterus, bone, liver, pituitary
• Toremifene: Newer congener of tamoxifen
• Raloxifene: Partial agonist at bone and CVS,
Antagonist in endometrium, breast
• Ormeloxifene: Supress endometrial
proliferation
Aromatase inhibitors
• Letrozole, anastrozole, exemestane
• Orally active
• Reversible inhibitor
• Early breast cancer: Adjuvant therapy after
mastectomy in ER +ve cases
• Advanced breast cancer
• ADR: Dyspepsia, thinning of hair, joint
pain, risk of thromboembolism
PROGESTINS
These are
substances which convert the estrogen primed endometrium to secretory and
maintain pregnancy (Progestin = favouring pregnancy)
Natural progestin
Progesterone, a 21 carbon steroid, is the natural progestin
• Derived
from cholesterol.
• Secreted by
the corpus luteum (10–20 mg/day) in the
later half of menstrual cycle under the influence of LH
• Production
declines a few days before the next menstrual flow
• If the ovum
gets fertilized and implants—the blastocyst mmediately starts producing
chorionic gonadotropin which is absorbed and sustains the corpus luteum in early pregnancy.
• Placenta
starts secreting lots of estrogens and progesterone from 2nd trimester till
term.
Synthetic progesterone
• Progesterone
derivatives (21C) – Medroxy progesterone acetate, megestrol acetate,
dihydrogesterone, hydroxyl progesterone caproate, nomegestrol acetate
• 19 –
Nortestosterone derivative (18C)Norethindrone (Norethisterone), lynestrenol
(ethinyl estrenol), allyl estrenol, levonorgestrel (Gonane)
• Newer
compounds – Desogestrel, norgestimate, gestodene
Actions of estrogen
Uterus:
• Preparation
of uterus for nidation and maintenance of pregnancy
• Prevention
of endometrial shedding, decrease uterine motility, inhibition of immunological
rejection of foetus
• Secretory
changes in estrogen primed endometrium, hyperemia, tortuocity of glands
• Decreases
sensitivity of myometrium to oxytocin
Cervix:
Progesterone
converts the watery cervical secretion induced by estrogens to viscid, scanty
and cellular secretion which is hostile to sperm penetration
Vagina:
Induces
pregnancy like changes in the vaginal mucosa—leukocyte infiltration of cornified
epithelium
Breast:
• Progesterone
causes proliferation of acini in the mammary glands
• Along with
estrogens, it prepares breast for lactation
• Withdrawal
of these hormones after delivery causes release of prolactin from pituitary and
milk secretion starts
CNS:
High
circulating concentration of progesterone (during pregnancy) appears to have a
sedative effect
Body
temperature: Slight increase (Hypothalamus thermostat) Respiration: High dose
stimulate respiration
Metabolism: Progestins
with androgenic effect increase LDL, decrease HDL Pituitary: Weak inhibitor of
Gonadotropin secretion
• Hypothalamus
decreases the frequency of LH pulses
• Prevents LH
surge and ovulation
Pharmacokinetics
• Orally high
FPM
• Liver –
Pregnanediol
• Glucuronic
acid and sulfate conjugation
• Synthetis
progestins
– Orally
active
– Metabolised
slowly
– Half-life:
8 – 24 hrs
ADR
• Breast
engorgement, headache, rise in BT, edema, esophageal reflux, acne, mood swings
• Continuous:
Irregular bleeding/ amenorrhoea
• 19 nor
derivatives – atherogenesis
• In HRT – Increased
risk of breast cancer
• Blood sugar
– raise with potent agents
• Early
pregnancy – Masculinization of female foetus and other congenital abnormalities
Uses
• As
contraceptive
• HRT
•
Dysfunctional uterine bleeding
•
Endometriosis
•
Premenstrual syndrome
• Threatened/
habitual abortion
• Endometrial
carcinoma
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