Estrogens and progestogens are the major female sex hormones. Estrogen acts in the proliferative phase of the endometrium while progesterone acts in the secretory phase and maintains pregnancy. Their synthesis is regulated by the hypothalamic-pituitary-ovarian axis and they have both genomic and non-genomic mechanisms of action by binding to estrogen and progesterone receptors in target tissues. Selective estrogen receptor modulators (SERMs) have tissue-specific agonist and antagonist effects on estrogen receptors and are used to treat breast cancer, osteoporosis, and infertility.

1. B.Manikanta
Asst.Professor,
Dept.Pharmacology,
IQ City Medical College,
Durgapur.

2. Synthesis and regulation of female sex hormones
Hypothalamus
GnRH
Anterior pituitary
FSH LH
Ovary
GF CL
Oestrogen Progesterone
-Ve-Ve
-Ve
+Ve
+Ve
GnRH agonistsGnRH antagonists +Ve-Ve
Maturation
RelaxinPlacenta Inhibin
Inhibits FSH release
Relax & dilates cervix

4.  Estrogens & progestogens -female sex hormones.
 Estrogen –proliferative phase of endometrium.
 Progesterone- secretory phase of endometrium &
maintains pregnancy.

5.  Major site for E,P synthesis-
o Non-pregnant pre menopausal women -- ovaries.
o Pregnancy-Foetal placental unit.
 Minor/Peripheral sites –liver, kidney, brain, adipose,
Sk.muscle & testes.
 Post.M.W-ovarian induced steroid synthesis-declines.
 Estradiol-most abundant estrogen- Pre.M.W.
 Estrone-most abundant estrogen- Post.M.W.
 Progesterone-by corpus luteum & placenta.

6. Estrogen preparations
1.Natural estrogens
 Estradiol-I.M/Depot/TDS/Cream.
 Estrone & Estriol (weaker E).
2.Synthetic steroidal estrogens-
 Ethinyl Estradiol
 Mestranol(prodrug)
 Quinesterol & Tibolone
3.Synthetic non-steroidal estrogens-
 Stilbestrol, Dienestrol, Chlorotrianisene.
4. Conjugated estrogens-(79.5-88%)
• Mixture of sod. estrone so4 & sod.equiline so4.

7. Protein binding
Estrogens- strongly binds to SHBG & albumin.
Estrogen bounded SHBG- pharmacologically inert
& can’t diffuse into cell.
Progesterone-binds to corticosteroid-binding α
globulin & albumin.
Free form of estrogen & progesterone can enter
the cell & binds to ER/PRs.

8. Estrogen/progesterone Receptor Types
ER-α -uterus, vagina, breasts, hypothalamus,
pituitary & blood vessels.
ER-β – prostrate & ovaries.
E. mediates its response through genomic & non-
genomic.
Non-genomic estrogen actions mediated thru’ ER-α .
i.e. + eNOS-vasodilation & cardio protective.
 Estrogen + synthesis of PRs & potentiate its response.
PR α,β- confined to female genital tract, breast,
hypothalamus & pituitary.
 Progesterone-X synthesis of ERs & limits its response.

9. PK of estrogens
Estrogens are available as Oral, parental, TDS & creams.
Natural E are not effective orally due to 1st pass effect.
Natural E undergo glucuroinde & So4conjugation .
Excreted through urine.
It undergoes E.H.C. & therefore exhibits hepatic to
peripheral S/E like thromboembolism, hepatic adenomas.
Synthetic estrogens-orally active.

10. Mechanism of Action of Steroid Receptors
Binding protein
Steroid
R
Gene Transcription
RNA
mRNA
Protein
Co activator/ Corepressor
proteins are required for gene
transcription.

11. Menopause-menstrual cycle is ceased.
• Ovarian function declines.
• No progesterone synthesis.
• Estrogen synthesis only 10% in P.M.W.
• Menopausal symptoms are more sever after
oophorectomy > natural menopause.
• HRT is advised- either E /+P.

12. Life span of female
Menarche Menopause
Delayed puberty Contraception
Dysmenorrhoea
DUB
P.M-HRT
Senile
vaginitis
Therapeutic uses of estrogens

13. 1. HRT- for post menopausal symptoms
a) Osteoporosis
b) Vasomotor symptoms
c) CVD/symptoms
d) Urogenital atrophy
e) Neuroprotective & CNS effects
2.ERT in primary ovarian failure
3.Dysfunctional uterine bleeding
4.Dysmenorrhoea
5.Acne & Hirustism
6.Prostrate carcinoma, Migraine & Colon cancer
Therapeutic uses of estrogens

14. 1.HRT- for post menopausal symptoms
A) Osteoporosis Rx-
 Conjugated equine estrogens(0.625mg/day).
 Estradiol-T.D patch.
 E(cyclic)+ P- to control endometrial proliferation.
 Bisphosphonates - Alendronate as alternative.
 Vit-D ,Calictonin & PTH supplements.
 Raloxifene-D.O.C.
 ERT in woman with intact uterus-?
 ERT in hysterectomy woman-?
 Endometrial biopsies-every year.

15. B) Vasomotor symptoms-
 Hot flushes are most common in P.M.W
 Release of LH due to E–nce.
 Short term RX with conjugated equine estrogen.
 Why short term therapy ?
 Medroxy progesterone - is effective.
 Clonidine-in E dependent tumours.
α2 agonists- central symp. outflow .

16. C) CVS-
 E-protective effect on lipid profile.
 Less incidence of CAD in Pre.M.W.
 High incidence in PMW.
 So Rx with Estradiol or conjugated estrogens.
 HRT for CAD is not advised becoz of A/E’s.
D) Urogenital atrophy- GUTI, painful intercourse.
 Rx with minimum doses of E+ P.
E)Neuroprotective/CNS effects –
 Insomnia, fatigue-lessen by ERT(alone).
 ERT-improves cognitive impairment & A.D-?

17. A/E of HRT -
 Venous thromboembolism.
 Gall stones.
 Uterine bleeding.
 Mood changes.
 Breast cancer, Migraine.
Tibolone -has estrogenic, progestogenic & weak
androgenic activities.
 Don't cause endometrial proliferation.
 It can be used continuously without cyclic P.
 Dose-2.5mg/daily-suppress PM. symptoms & Gn levels.

18. 2.ERT in primary ovarian failure(P.O.F)-
 POF is due to ovarian dysgensis or hypopitutarisim/Turner synd.
Life span of Female
Delayed puberty
Menopause
E-0.01mg-3wks of every
month for 4months.
E-0.02mg-3wks of every
month for 1yr.
P-last wk of every month-
induce regular menses.
Androgens/GH-added for
height & normal growth.
ERT is started at 11-13yrs of age with small doses.
Menopuse-20ovarian failure.
Menarche
When pubertal & sexual characteristics
develops, P should be started.
4M 1 wk 2wk 3 wk 4 wk
1Yr

19. 3.DUB-is unpredictable & painless uterine bleeding due to
chr.anovulatory cycles. 3types-
a) E.withdrawal bleeding-Rx ERT / high dose E containing
O.C pills for 3wks.
b) E. breakthrough bleeding-Polycystic ovarian.syn
c) P. breakthrough bleeding-using low doses O.C.pills
b & c- Rx high doses P therapy.
Recurrence can be stopped by cyclic O.C. pills for 3months.
4. Dysmenorrhoea-PG’s Syn’s by endometrium.
 Rx by NSAIDs-1st line drugs.
 Combined E + P therapy-to suppress ovulation.
- causes anovulatory cycles.

20. 5. Senile vaginitis –Dyspareunia & urethral syndrome
well responds to topical E therapy.
 Antibacterial-as adjuvant.
e.g.- Kraurosis vulvae.
6. Acne & Hirustism-
 Acne-due to androgen secretion.
 Cyclic Rx of E+P = suppress ovarian androgens by
X GnH release from the pituitary.
 Topical therapy-antibiotics, tretinoin -preferred.

21. E. also suppress ovarian androgens production by X
LH secretion- helps in reducing hirsutism.
7. Carcinoma prostrate- T dependent tumour.
 E X pituitary LH secretion(-Ve feedback)---X T
production.
 Fosfestrol – prodrug of E, conc. in testis.
Fosfestrol Stilbestrol
 GnRH agonists+/ Androgen antagonists-preferred.
T=Testosterone
Phosphatase in prostrate tissue

22.  Males-
 Gynaecomastia,
 Feminisation,
 Decreased libido (RX prostrate carcinoma).
 Females-
 Breast tenderness,
 Migraine,
 Withdrawal bleeding,
 Amenorrhoea,
 Endometrial hyperplasia,
 Risk of breast cancer,
 Vaginal & Cervical adrenocarcinoma(female off spring).
 In both sexes- Gall stones, Gall bladder diseases, Hepatic
dysfunction, Thromboembolic disorders, diabetes, Fluid retention.
Estrogen :Adverse effects

23.  Gall bladder diseases
 Thromboembolic disorders
 Pregnancy
 Hepatic dysfunction
 Diabetes
 Estrogen dependent breast carcinoma
 Endometrial carcinoma
 Endometriosis
 Undiagnosed Genital bleeding.
{ GTP-HEDG }
Estrogen : contraindications

24. Estrogens: Drug interactions
-GUT microbial flora.
-EHC of estrogens
-High doses are required.
-Increases metabolism
-Decreases effectiveness
-Should be increased.
2.Enzyme inducers-
3.Dose-of insulin & oral hypoglycaemic agents
1.Antibiotics reduces-

25. Synthetic & non-steroidal.
Selectively acts on ER-
 Agonist -
• Estrogenic,
• Beneficial effects on -
 Antagonist-
• Antiestrogenic
• Blocks estrogenic effects on
e.g. Clomiphene, tamoxifen, doloxifen, toremifen,
fluvestrant, raloxifene, ormeloxifen.
SERMS
Bone, Brain, Liver
Breast,
Endometrium

26. Clomiphene (C)-
 Orally active SERM.
 Competitive antagonists of ER in hypothalamus.
M.O.A- Clomiphene citrate
Competitively blocks both E.R α,β.
opposes/abolishes the –ve feedback effect of E.
stimulates Gn (FSH/LH) secretion
induces ovulation.

27. Uses-
1.Infertility due to anovulation-
MENSTRUAL CYCLE
Day 1
Day 28
 50mg should be taken from 5th day of cycle, OD
X 5days.
Cyclic therapy is recommended.
It should not be used more than 6 cycles becoz
of ovarian cancer.
If conception doesn't occur-double the dose-
200mg/day for 2-3cycles.
Clomiphene with menotropins/HCG- success rate
Its of no use in 10 ovarian and pituitary failure.

28. 2.Male infertility due to oligozoospermia
- Gn secretion.
- promotes T & spermatogenesis.
Rx-25mg/day X 24days in a month with 6 days rest & continued for 6
months.
3.Along with gonadotropins
- to improve maturation & harvesting of ova for
in vitro fertilization.
A/E- multiple pregnancy, ovarian enlargement, polycystic ovaries, hot
flushes, wt. gain, alopecia, vertigo.

29. Tamoxifen
E.R Agonist
uterus liverBone Pituitary
Endometrial
carcinoma
Bone density
Prevents P.M
Osteoporosis
due to TGF β
HDL LDL
CAD risk
E.R Antagonist
Breast
X Carcinoma
RX of breast cancer
in both Pre & Post.M.W.
Response to E.R +ve
breast cancer,
Male breast cancer
Due to up regulation of
TGF-β
Blood
vessels
Deep vein
thrombosis
Peripheral
sites
Hot flushes

30. • Hot flushes
• Vomiting
• Menstrual irregularities
• Anorexia
• Mild leucopoenia & Ocular effects.
Doloxifen and Toremifen-
• Similar to tamoxifen.
Fulvestrant –I.M inj every month
• No agonist,
• E R Antagonist-longer acting,
• Tamoxifen resistant cases breast cancer.
Adverse Effects of Tamoxifen

31. Raloxifene
 Poor oral B.A & under goes 1st pass.M.
 t1/2-28-30hrs. Dose-60mg/day
 A/E-hot flushes, deep vein thrombosis, pulmonary embolism.
E.R Agonist E.R. Antagonist
Bone
RX of P.M.
Osteoporosis
Endometrium
Inhibits endometrial
proliferation
Blood
coagulation
Breast
Risk of breast
cancer 60-70%
Deep vein thrombosis
Pulmonary embolism
Favourable
lipid profile
Liver
E.R + ve breast
cancer

32. Ormeloxifen
A/E- Nausea, headache, fluid retention & weight retention.
E.R.
Antagonist
Anti progestin
Breast uterus
Less Estrogenic
(agonist)
Rx of DUB, associated with
anovular cycles occurring near
menopause
RX. Br.
carcinoma
Non-hormonal
contraceptive
•RX of osteoporosis
•RX of endometrial
carcinoma
Under investigation

33. Estrogen Synthesis inhibitors
Testosterone Estradiol
1St gen 2nd gen
Uses-
 ER expressing Br.carcinoma
 Resistant to tamoxifen
 Along with androgen antagonists- Rx of precocious
puberty
 10 treatment of excessive aromatase syndrome.
A/E-hot flushes, joint pain, thromboembolic disease.
Aromatase
Aromatase
inhibitors
Amino glutethimide
Selective &
Steroidal
Formestane
Exemestane
Non-steroidal
Anastrazole
Letrozole
Fradrozole
Vorozole

34. Progestins-pharmacokinetics
Orally ineffective-1st pass.M
T1/2-5-7mins.
Metabolised to pregnanediol & excreted-urine.
Micronized progesterone formulation.
Synthetic progestins are orally active.
 Long t1/2 life ranges from 10-24hrs.
 Duration lasts for 1-3days.

35. Progestin preparations
Newer
19-Nortesterone
derivatives
19-Nortesterone
derivatives
Progesterone
analogues
Hydroxy progesterone
Medroxy progesterone
Megesterol acetate
Dihydrogesterone
Nomegestrol*
Pure progestins
Weak androgenic &
Antiovulatory
HRT in P.M.W
Threatened abortion
Endometriosis- for
selective p effect
Contraceptive along
with estrogens
Progestogenic , Anabolic
Weak androgenic &
estrogenic
Potent Antiovulatory
activity
Don't antagonise the
beneficial effects of E.
Contraceptives along
with estrogens.
Lipid friendly.
Rx of hyperandrogemia.
Potent & pure progestins
No androgenic
Strong Antiovulatory
activity
Along with oestrogen
Norethisterone
Norethynodrel
Ethinylesterol
Norgestrel
Levonorgestrel*
Desogestel*
Norgestimate*
Gestodene

36. Life span of female
Menarche Menopause
Contraception.
DUB
Endometriosis
Postponement
of periods
HRT(adjuvant)
Endometrial
carcinoma
USES OF PROGESTINS

37. Progestins: Therapeutic uses
1. HRT- P lacking androgenic activity is preferred & given
with E in cyclic manner.
 To counter act the risk of E. carcinoma due to E.
2 .Hormonal contraception.
3.Rx of DUB.
 Norethindrone (20-40mg/day)- stops bleeding.
 Given along with cyclic Rx of E -regularises the
menstrual flow.
 P with estrogenic activity is preferred so that E dose can
be reduced.

38. 4.Endometriosis-
 Its due to +nce of ectopic endometrial cells.
 Manifestations - dysmenorrhoea, painful pelvic
swelling, infertility.
 P inhibits ectopic endometrial cells proliferation.
 Continued use of progestins induces anovulatory,
hypoestrogenic – Gn release .
 progestin therapy is effective & cheap.
 Danazol is used as alternative.
 GnRH agonists & Antiprogestins.

39. 4.Endometrial carcinoma- palliative in advanced &
metastatic cases.
 High doses of progestins are required to stop metastasis.
5.Threatened/ habitual abortions-
 1st trimester- Pure P without E/androgenic activity.
6.Diagnosis- by MDPA (10mg/day/oral/1wk)
A) for E secretion B) for endometrial responsiveness- in
amenorrhoeic women.
7.Premature labour & infertility
(Luteal support in Luteal dysfunction cases).

40. 8.Premenstrual tension-
 Headache, irritability, fluid retention, breast tenderness
are observed few days before menstruation.
 P.M.dysphoric disorder-(depression predominates)
 Rx by Fluoxetine & SSRI’s- irritability & mood changes.
 Sever cases-suppression of ovulation by cyclic Rx of E+ P
is very effective & PGF2α release of during
ovulatory cycle.

41. 9.Post pone of periods-
 Either P/ +C.O.C. Pills should be started 5 days before
the expected period & continued till required.
 Withdrawal bleeding occurs in 72hrs after stoppage of
the drug.
-A/E:-
 Breast engorgement, fever, head ache,
 fluid retention, depression,
 irritability, acne, wt. gain, diabetes (Norgestrel)
 Decreased libido, Irregular M. cycle,
 Thromboembolism, atherogenesis (Norgestrel)
 Masculinisation & congenital abnormalities.
 P in HRT as long term-risk of breast cancer.

42. C.I:-
 Depression
 Pregnancy-due to Virilization of foetus
 genital abnormalities.
D.I:-
E.inducers - decreases the effects of progestin by
increasing in metabolism.

43. Antiprogestin- Mifepristone
 Its a synthetic steroidal derivative
 Competitively binds peripheral P.R & blocks
progesterone effects.
 Its a partial agonists & competitive antagonist.
 Its a potent Antiprogestin- act as contragestational agent


44. Mifepristone
Blocks
P.Receptors
Contragestational
agent
Blocks
progesterone
support to
endometrium
Endometrial
shedding
PG release
Pregnancy
termination
Uterine
contractions
Sensitises the
myometrium
to P.Gs
Facilitates menstruation
Conceptus detached
from uterine wall
HCG levels declines-20 Luteolysis
Decreases the
progesterone
secretion
Softens
the cervix
Favourable
for Abortion
Antiandrogenic
&
Antiglucorticoid
Rx Cushing
syndrome

46. Mifepristone Uses
1. Termination of pregnancy- up to 7wks.
 Mifepristone(600mg,orally) + Misoprostol(400mg
orally) / Gemeprost (1mg as pessary).
 Midterm abortion-(13-24wks)-Mifepristone +
Gemeprost.
 If adm within 10days of missed period results heavy
period.
 Its not effective after 7wks, becoz later placenta starts
enough P to over come the antiprogestin effects of
mifepristone.

47. 2.Postcoital contraceptive-
 Mifepristone -within 72hrs of intercourse, interferes
with implantation.
 Effective method for emergency contraception.
3.Softening cervix-Mifepristone soften & dilates cervix,
prior to surgical abortion/ labour induction.
4.For induction of labour- intrauterine foetal death.
5.Endometriosis.
6.Uterine fibroids.
7.Progesterone dependent brain neoplasm.
8.Breast cancer.
9. Cushing's syndrome- as a palliative.

48. S/E:- abortion failure, prolonged bleeding, abdominal
cramps, vomiting, diarrhoea & anorexia.
D.I- with E.inducers/inhibitors are observed.
Onapristone- newer Antiprogestin & effective.
Gestinone -Rx of Endometriosis

49. TOGETHER WE CAN MAKE A DIFFERENCE
Than
Q
U