2. FEMALE REPRODUCTIVE SYSTEM
⢠Internal sex organs
Uterus
Fallopian tubes
Ovaries
⢠External sex organs
The labia
Clitoris
Vaginal opening
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4. MENSTRUALCYCLE
⢠The menstrual cycle is the regular natural change that occurs in
the female reproductive system (specifically the uterus and
ovaries) that makes pregnancy possible.
⢠Menarche - The first period usually begins between twelve and
fifteen years of age.
⢠Menopause - Menstruation stops at this point
⢠Includes two cycles
Ovarian cycle - Follicular phase, Ovulation, Luteal phase
Uterine cycle - Menstruation, Proliferative phase, secretory
phase
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8. REGULATION OF SECRETION
⢠Daily Secretion â 10 - 20Îźg
⢠Follicular Phase â FSH Estrogen
⢠After ovulation - Corpus luteum continues to secrete
estrogens till about two days before menstruation.
⢠During pregnancy - Placenta secretes large quantities
of estrogens.
⢠In the postmenopausal women - 2â10 Îźg secrete daily.
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10. MECHANISM OFACTION OFESTROGEN
⢠Estrogen receptors (Ers) â Nuclear receptors.
⢠ERι , Erβ
⢠Erι - Uterus, Vagina, Breast, Bone, Hypothalamus and Blood vessels.
⢠Erβ - Prostate gland of males and Ovaries in females.
⢠ER + Ligand Dimeraization Interaction of EREs of target
genes Gene transcription.
⢠If an antagonist is bind Differ the conformation due to the
Corepressor protein and Inhibit gene transcription.
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11. PHARMACOLOGICAL ACTION
1. SEX ORGANS
ďPubertal changes
ďProliferation of endometrium
ďMensrual cycle
ďContractions of the fallopian tubes and uterus
ďInduce a watery alkaline secretion from the cervix
ďAtrophic changes - After menopause
2. SECONDARY SEX CHARACTERS
ďEstrogens produced at puberty.
ďAcne - Administration of estrogens to suppress pituitary-gonadal axis causes
regression of acne.
3.METABOLIC EFFECT
ďIt promotes positive calcium balance.
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12. ďSalt and water retention.
ďGlucose tolerance - Combination contraceptives containing higher doses of
estrogens and progestins.
ďEstrogens induce nitric oxide synthase and PGI2 production in vascular
endothelium.
4. CARDIOVASCULAR DISEASES
ďReduce the risk of cardiovascular disease.
ďOral estrogens - Increase the risk of thromboembolic disease.
5. EFFECTS ON COGNITION
ďIncrease cognition and delayed the onset of Alzheimerâs disease.
6. OTHER POTENTIAL UNTOWARD EFFECTS
ďNausea and vomiting.
ďBreast fullness, tenderness, edema.
ďCause severe migraine, Endometriosis.
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13. PHARMACOKINETICS
ďEstrogens are well absorbed orally and transdermally.
ďNatural estrogens are inactive by the oral route due to rapid
metabolism in liver.
ďEstradiol esters injected i.m. are slowly absorbed and exert
prolonged action.
ďEthinyl estradiol is cleared more slowly than is estradiol due to
decreased hepatic metabolism.
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14. THERAPEUTIC USES
1.MENOPAUSAL HORMONE THERAPY (MHT) AND
HORMONE REPLACEMENT THERAPY (HRT)
ďˇVasomotor Symptoms
ďˇOsteoporosis
ďˇVaginal Dryness and Urogenital Atrophy
ďˇCardiovascular Disease
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15. ďśMENOPAUSAL HORMONE REGIMENS, Estrogen-
replacement therapy, or ERT
⢠Estrogens alone therapy
Postmenopausal women was associated with an increased
incidence of endometrial carcinoma.
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16. ďśESTROGEN TREATMENT IN THE FAILURE OF
OVARIAN DEVELOPMENT
⢠In several conditions (e.g., Turnerâs syndrome) - Ovaries
do not develop and puberty does not occur.
⢠Estrogen therapy at the appropriate time replicates the
events of puberty.
⢠Androgens and/or Growth hormone may be used
concomitantly to promote normal growth.
⢠Estrogens and Androgens promote bone growth, they also
accelerate epiphyseal fusion.
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17. 2. SENILE VAGINITIS
3. DELAYED PUBERTY IN GIRLS
4. DYSMENORRHOEA
5. ACNE
6. DYSFUNCTIONAL UTERINE
BLEEDING
7. CARCINOMA PROSTATE
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18. ADVERSE EFFECT
ďMales - Suppression of libido, gynaecomastia and feminization
ďChildrens - Fusion of epiphyses and reduction of adult stature
ďIn postmenopausal women - Risk of iregular bleeding and endometrial
carcinoma
ďAccelerate the growth of existing breast cancer
ďLong-term therapy - Doubles the incidence of gallstones.
ďMigraine, epilepsy and endometriosis.
ďStilbestrol given to pregnant women- increased the incidence of vaginal
and cervical carcinoma in the female offspring in childhood or early
adulthood.
ďEstrogens are contraindicated during pregnancy.
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19. ANTIESTROGENS
1.Clomiphene citrate
MECHANISM OF ACTION
ďIt binds to both ERÎą and ERβ.
ďIt induces Gn secretion in women.
ďAntagonism of peripheral actions of estrogen results in hot flushes.
ďEndometrium and cervical mucus may be modified.
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20. ⢠Oligospermia
⢠To aid in vitro fertilization
Clomiphene given with Gns causes synchronous maturation
of several - Harvesting for in vitro fertilization.
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21. ADVERSE EFFECT
⢠Polycystic ovaries
⢠Multiple pregnancy
⢠Hot flushes
⢠Gastric upset
⢠Vertigo
⢠Allergic dermatitis
⢠Risk of ovarian tumour
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22. 2. Fulvestrant
⢠âSelective estrogen receptor down-regulatorsâ
(SERDs)
⢠âPure estrogen antagonistsâ
⢠Treatment of breast cancer in postmenopausal
women
⢠It inhibits ER dimerization - ER interaction
with DNA is prevented - Receptor
degradation The ER is thus down regulated -
Suppression of ER responsive gene function.
⢠250 mg monthly i.m. injections in the buttock.
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23. SELECTIVE ESTROGEN RECEPTOR MODULATORS
(SERMs)
⢠Antiestrogenic actions & Estrogenic action.
1. TAMOXIFEN CITRATE
⢠Potent estrogen antagonist - Breast carcinoma cells, blood vessels ,
peripheral sites.
⢠Partial agonist - Uterus, bone, liver, pituitary.
⢠Antiestrogenic action â
ďźInhibition of human Breast cancer cells.
ďźInhibition of Hot flushes
⢠weak estrogen agonistic action â
ďźStimulation of endometrial proliferation,
ďźLowering of Gn and prolactin levels in postmenopausal women .
ďźImprovement in their bone density.
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24. ADVERSE EFFECT
⢠Hot flushes, vomiting, vaginal bleeding, vaginal discharge,
⢠Menstrual irregularities
⢠Increased risk of venous thromboembolism - Estrogenic action
on clotting mechanism.
⢠Dermatitis
⢠Anorexia
⢠Depression
⢠Mild leucopenia
⢠Ocular changes are infrequent.
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25. 2. Raloxifene
ďEstrogen partial agonist - Bone and Cardiovascular system
ďAntagonist - Endometrium and Breast.
ďIt has high affinity for both ERÎą and ERβ.
ďIt has a Distinct DNA target the âraloxifene response elementâ (RRE).
ďPrevents bone loss in postmenopausal women.
ďBone mineral density (BMD) may even increase.
ďRaloxifene reduces LDL cholesterol, - Up regulating hepatic LDL receptors.
ďIt does not stimulate endometrial proliferation - No increase in the risk of
endometrial carcinoma.
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26. ⢠ADVERSE EFFECTS
ďHot flushes
ďMild leg cramps
ďVaginal bleeding is occasional.
ďDeep vein thrombosis and pulmonary embolism.
⢠THERAPEUTIC USES
Second line drug for prevention and treatment of
Osteoporosis in postmenopausal women - Ca2+ and vit D
supplements enhance the benefit.
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27. AROMATASE INHIBITORS
⢠Aromatization of âAâ ring of testosterone is the final and key
step in the production of estrogens (estradiol/estrone) in the
body.
⢠These drugs are inhibit the final step.
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28. 1. Letrozole
⢠It is an orally active nonsteroidal
⢠compound that reversibly inhibits aromatization all over the
body - estrogen deprivation.
⢠Not to be used in menopausal women
⢠Most effective in early stage breast cancer.
⢠No endometrial hyperplasia.
⢠Accelerate bone loss, predisposes to fracture, arthritic
symptoms.
⢠No increase in thromboembolic risk.
⢠No effect in lipid profile.
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29. ADVERSE EFFECTS
⢠Hot flushes,
⢠nausea, diarrhoea,
⢠dyspepsia and thinning of hair
⢠Joint pain
⢠bone loss may be accelerated.
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30. 2. Anastrozole
⢠Another nonsteroidal and reversible drug.
⢠Used to treat breast cancer.
SIDE EFFECTS
⢠Hot flushes
⢠Vaginal dryness
⢠Vaginal bleeding
⢠Nausea, diarrhoea
⢠Thinning of hair
⢠Arthralgia
⢠Acceleration of osteoporosis
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31. PROGESTINS
Natural progestins
⢠It is secreted by the corpus luteum (10â20 mg/day) - Later half of menstrual
cycle under the influence of LH.
⢠Its production declines a few days before the next menstrual flow.
⢠If the ovum gets fertilized and implantsâ Placenta starts secreting lots of
estrogens and progesterone from 2nd trimester till term.
⢠Men produce 1â 5 mg progesterone per day from adrenals and testes; its role
if any, in males is not known.
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33. MECHANISM OFACTION
⢠Progesterone receptor (PR) has a limited distribution in the
body: female genital tract, breast, CNS and pituitary.
⢠The PR is normally present in the nucleus of target cells.
⢠Analogous to ER
⢠PR + Ligand Dimerization attaches to progesterone
response element (PRE) of target genes regulates
transcription through coactivators.
⢠The antiprogestins also bind to PR, but the conformation
assumed is different from agonist bound receptor and opposite
effects are produced by interaction with corepressors.
⢠The PR exists in a short (PR-A) and a longer (PR-B) isoforms.
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34. PHARMACOLOGICALACTION
1. Uterus
ďSecretory changes in the estrogen primed
endometrium.
ďHyperemia, tortuocity of glands and increased.
ďContinued action of progesterone (when
pregnancy occurs) brings about decidual
changes in endometriumâstroma enlarges
and becomes spongy, and sensitivity of
myometrium to oxytocin is decreased.
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35. ⢠Cervix
⢠Vagina
⢠Breast
⢠CNS
⢠Body temperature
⢠Respiration
⢠Metabolism
⢠Pitutary
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36. THERAPEUTIC USES
1. As contraceptive Most common use
2. Hormone replacement therapy (HRT)
3. Dysfunctional uterine bleeding
4. Endometriosis
5. Premenstrual syndrome/tension
6.Threatened/habitual abortion
7.Endometrial carcinoma
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37. ADVERSE EFFECT
⢠Breast englargement,headache, rise in body temperature, edema,
esophageal reflux, acne and mood swings may occur with higher
doses.
⢠Irregular bleeding or amenorrhoea can occur if a progestin is
given continuously.
⢠Lower plasma HDL levelsâmay promote atherogenesis
⢠Long-term use of progestin in HRT may increase the risk of
breast cancer.
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38. ⢠Blood sugar may rise and diabetes may be precipitated
⢠Intramuscular injection of progesterone is painful.
⢠Given in early pregnancy, progestins can cause masculinization
of female foetus and other congenital abnormalities.
⢠Use of a progestin for diagnosis of pregnancy is contraindicated
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39. ANTIPROGESTINS
1. Mifepristone
⢠Potent antiprogestational and significant antiglucocorticoid,
antiandrogenic activity.
⢠Given during the follicular phase â slowing of follicular
development and delay/failure of ovulation.
⢠If given during the luteal phase â prevents secretory changes
by blocking progesterone action on the endometrium.
⢠Later in the cycle, it blocks progesterone support to the
endometrium, unrestrains PG release from itâthis stimulates
uterine contractions.
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40. ⢠Mifepristone also sensitizes the myometrium to
PGs and induces menstruation.
⢠If implantation has occurred, it blocks
decidualization - HCG production falls -
Secondary luteolysis occurs - Endogenous
progesterone secretion decreases - Cervix is
softened. All these effects lead to abortion.
⢠It is a partial agonist and competitive antagonist
at both A and B forms of PR.
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41. THERAPEUTIC USES
â˘Termination of pregnancy
7 weeks - 600 mg as single oral dose causes
complete abortion.
â˘Cervical ripening
24â30 hours before attempting surgical
abortion or induction of labour,
mifepristone 600 mg results in softening of
cervix.
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42. ⢠Postcoital contraceptive
Mifepristone 600 mg given within 72 hr of intercourse interferes with
implantation,
⢠Once-a-month contraceptive
ďźA single 200 mg dose of mifepristone given 2 days after mid cycle
each month prevents conception on most occasions.
ďźAdministering mifepristone in late luteal phase to dislodge the
embryo (if present) .
⢠Induction of labour
ďźBy blocking the relaxant action of progesterone on uterus of late
pregnancy
ďźMifepristone can promote labour.
ďź It may be tried in cases with intrauterine foetal death and to deliver
abnormal foetuses
⢠Cushingâs syndrome
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43. 2. Ulipristal
ďźIt is a recently approved âselective progesterone receptor
modulatorâ (SPRM) .
ďźEmergency contraceptive.
ďźIt inhibits ovulation by suppressing LH.
ďźIts action on endometrium can interfere with implantation.
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45. REFERENCES
⢠The Pharmacological basis of Therapeutics, 12th edition by
Goodman and Gillman.
⢠Essentials of Pharmacology, 7th edition by K D Tripathi.
⢠Principles of Anatomy and Physiology by Gerard J Tortora and
Bryan Derrickson.
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