Female sex hormones

1. FEMALE SEX HORMONES
AYANA R KUMAR
M. Pharm, Pharmacology
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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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6. FEMALE SEX HORMONES
• Estrogens
• Progestins
ESTROGENS
• Natural estrogens
Estradiol
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7. Synthetic estrogens
Steroidal -Ethinylestradiol, Mestranol, Tibolone.
Nonsteroidal - Diethylstilbestrol (stilbestrol), Hexestrol,
Dienestrol.
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8. REGULATION OF SECRETION
• Daily Secretion – 10 - 20μg
• Follicular Phase – 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 - 2–10 μg secrete daily.
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10. MECHANISM OFACTION OFESTROGEN
• Estrogen receptors (Ers) – Nuclear receptors.
• ERα , Erβ
• Erα - 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
Pubertal changes
Proliferation of endometrium
Mensrual cycle
Contractions of the fallopian tubes and uterus
Induce a watery alkaline secretion from the cervix
Atrophic changes - After menopause
2. SECONDARY SEX CHARACTERS
Estrogens produced at puberty.
Acne - Administration of estrogens to suppress pituitary-gonadal axis causes
regression of acne.
3.METABOLIC EFFECT
It promotes positive calcium balance.
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12. Salt and water retention.
Glucose tolerance - Combination contraceptives containing higher doses of
estrogens and progestins.
Estrogens induce nitric oxide synthase and PGI2 production in vascular
endothelium.
4. CARDIOVASCULAR DISEASES
Reduce the risk of cardiovascular disease.
Oral estrogens - Increase the risk of thromboembolic disease.
5. EFFECTS ON COGNITION
Increase cognition and delayed the onset of Alzheimer’s disease.
6. OTHER POTENTIAL UNTOWARD EFFECTS
Nausea and vomiting.
Breast fullness, tenderness, edema.
Cause severe migraine, Endometriosis.
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13. PHARMACOKINETICS
Estrogens are well absorbed orally and transdermally.
Natural estrogens are inactive by the oral route due to rapid
metabolism in liver.
Estradiol esters injected i.m. are slowly absorbed and exert
prolonged action.
Ethinyl 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)
Vasomotor Symptoms
Osteoporosis
Vaginal Dryness and Urogenital Atrophy
Cardiovascular Disease
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15. MENOPAUSAL 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. ESTROGEN TREATMENT IN THE FAILURE OF
OVARIAN DEVELOPMENT
• In several conditions (e.g., Turner’s 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
Males - Suppression of libido, gynaecomastia and feminization
Childrens - Fusion of epiphyses and reduction of adult stature
In postmenopausal women - Risk of iregular bleeding and endometrial
carcinoma
Accelerate the growth of existing breast cancer
Long-term therapy - Doubles the incidence of gallstones.
Migraine, epilepsy and endometriosis.
Stilbestrol given to pregnant women- increased the incidence of vaginal
and cervical carcinoma in the female offspring in childhood or early
adulthood.
Estrogens are contraindicated during pregnancy.
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19. ANTIESTROGENS
1.Clomiphene citrate
MECHANISM OF ACTION
It binds to both ERα and ERβ.
It induces Gn secretion in women.
Antagonism of peripheral actions of estrogen results in hot flushes.
Endometrium 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
• ‘Selective estrogen receptor down-regulators’
(SERDs)
• ‘Pure estrogen antagonists’
• 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 –
Inhibition of human Breast cancer cells.
Inhibition of Hot flushes
• weak estrogen agonistic action –
Stimulation of endometrial proliferation,
Lowering of Gn and prolactin levels in postmenopausal women .
Improvement 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
Estrogen partial agonist - Bone and Cardiovascular system
Antagonist - Endometrium and Breast.
It has high affinity for both ERα and ERβ.
It has a Distinct DNA target the ‘raloxifene response element’ (RRE).
Prevents bone loss in postmenopausal women.
Bone mineral density (BMD) may even increase.
Raloxifene reduces LDL cholesterol, - Up regulating hepatic LDL receptors.
It does not stimulate endometrial proliferation - No increase in the risk of
endometrial carcinoma.
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26. • ADVERSE EFFECTS
Hot flushes
Mild leg cramps
Vaginal bleeding is occasional.
Deep 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 ‘A’ 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 (10–20 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 implants— Placenta starts secreting lots of
estrogens and progesterone from 2nd trimester till term.
• Men produce 1– 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
Secretory changes in the estrogen primed
endometrium.
Hyperemia, tortuocity of glands and increased.
Continued action of progesterone (when
pregnancy occurs) brings about decidual
changes in endometrium—stroma 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 levels—may 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 → slowing of follicular
development and delay/failure of ovulation.
• If given during the luteal phase → 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 it—this 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
•Termination of pregnancy
7 weeks - 600 mg as single oral dose causes
complete abortion.
•Cervical ripening
24–30 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
A single 200 mg dose of mifepristone given 2 days after mid cycle
each month prevents conception on most occasions.
Administering mifepristone in late luteal phase to dislodge the
embryo (if present) .
• Induction of labour
By blocking the relaxant action of progesterone on uterus of late
pregnancy
Mifepristone can promote labour.
 It may be tried in cases with intrauterine foetal death and to deliver
abnormal foetuses
• Cushing’s syndrome
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43. 2. Ulipristal
It is a recently approved ‘selective progesterone receptor
modulator’ (SPRM) .
Emergency contraceptive.
It inhibits ovulation by suppressing LH.
Its action on endometrium can interfere with implantation.
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44. ADVERSE EFFECT
•Headache
•nausea, vomiting
•abdominal pain
•menstrual delay
•ovarian cysts
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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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46. THANK YOU
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