Estrogen, progestin, ocp

1. DRUGS USED IN REPRODUCTIVE HEALTH
Estrogens & Progestins
Oral Contraceptives
Uterine Stimulants
(Oxytocics)
•Oxytocin
•Methylergotmetrine
•Misoprostol
Uterine Relaxants
(Tocolytics)
•Ritodrine
•Nifedipine
•Isoxsuprine

3. ESTROGEN
•Female sex hormone
• Follicle Stimulating Hormone (FSH) stimulate the
production of Estrogens.
•Natural Estrogens:
•Estradiol (secreted by graafian follicles, corpus
luteum and placenta in females and by
aromatization of testerone in testes and
extraglandular tissues in males; most potent)
•Esterone (oxidised form of estradiol E2, in liver)
•Estriol (formed by hydroxylation of esterone)

4. Steroidal Non-Steroidal
Ethinylestradiol Diethylstilbestrol
Mestranol Hexestrol
Tibolone Dienestrol
SYNTHETIC ESTROGENS

5. Synthesis of Estrogens

6. Estrogen Functions
• Bring about pubertal changes- growth of uterus,
fallopian tubes and vagina
• Responsible for proliferation of endometrium
• Growth of uterine muscles
• Ductal proliferation in breast
• Secondary sexual characters in females

7. MOA: Estrogen binds to specific nuclear
receptors (Estrogen receptors, ER) and undergoes
conformational changes interacting with Estrogen
Response Elements, ERE that regulates protein
synthesis.

8. estrogen
ERE
estrogen

9. Actions of Estrogens:
Sex organs:
•Responsible for pubertal changes, growth of uterus,
fallopian tubes and vagina
•Enhances sperm penetration
Secondary Sex Characters:
•Breasts: proliferation of ducts and stroma, accumulation
of fat
•Pubic and axillary hair appears
Metabolic effects:
•Estrogens are anabolic hormone responsible for pubertal
growth in both boys and girls
Maintains bone mass; retards bone resorption; Promotes
fusion of epiphyses

10. • Water and salt retention; Blood pressure may rise on
prolonged use
• Glucose tolerance is impaired especially in diabetes
• Estrogens decrease plasma LDL cholesterol while HDL
and triglyceride levels are raised.
• Blood Coagulability is increased due to induction of
clotting factors
• Fibrinolytic activity increases (lowering of plasminogen-
activator inhibitor-I, PAI-I)
• Nitric oxide synthase and Prostaglandin I2 (PGI2 )
production promotes vasodilatation
• Increases lithogenicity of bile (increased cholesterol
secretion and decresed bile salt secretion)
• Increases Hormone Binding Globulin; Thyroxine Binding
Globulin (TBG), Cortisol Binding Globulin (CBG)
Actions of Estrogens contd…

11. Growth of
Epithelium
rate of bone
skin structure
Liver synthesis of
follilcle
Growth of
endometrium
Lowers
Plasma cholesterol
Behavioral effects
ESTROGENS
Reproductive Tissues
Vaginal Mammary
Gland
Decreases
resorption
Increases blood coagulability
Maintains normal
Reduces
Bowel motility
Sperm
transport
Transport Proteins
Ovarian
Non-reproductive Tissues
Physiology

12. The daily secretion of estrogens in menstruating women
varies from 10–100 μg depending on phase of the cycle.
During pregnancy, placenta secretes large quantities of
estrogens, (mainly estrone and estriol) upto 30 mg/day.

13. -12 -10-8 -6 -4 -2 0 2 4 6 8 10 12 14
MensesMenses
Menses
Ovulation
Follicular Growth Corpus Luteum
4
8
12
16
20
24
28
32
36
40
60
80
LHandFSH(mU/ml
)
Prog Estradiol
10
8
6
7
9
5
4
3
2
1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
(ng / ml)
P
E
E
FSH
F
LH
Regulation : Circulating Levels

16. Indication & Doses:
•Contraception
•Post menopausal hormone therapy
•Primary hypogonadism
•Dysmenorrhoea & Acne
•Carcinoma of prostate
•Advanced metastatic carcinoma of breast
•Senile vaginitis
•Inhibition of lactation
•Estradiol: 2.5-10mg intramuscular injection
•Ethinylestradiol: 0.02-0.2 mg/day, oral

17. Adverse effects:
•Males; Suppression of libido, gynaecomastia and
feminization
•Children; Fusion of epiphyses and reduction of adult
stature
•Postmenopausal women/ on HRT; Risk of irregular
bleeding and endometrial carcinoma
•Existing Breast cancer; Growth of existing breast cancer
•Long term estrogen therapy; gallstones,hepatoma
•Pregnant Women (esp. first trimester) Vaginal and cervical
carcinoma in female offspring

18. ANTIESTROGENS AND SELECTIVE ESTROGEN
RECEPTOR MODULATORS (SERMs)
Clomiphene citrate
•It binds to both ERα and ERβ and acts as a pure
estrogen antagonist in all human tissues.
•Useful for infertility due to failure of ovulation
and to aid in vitro fertilization.
•The chief use of clomiphene is for infertility due
to failure of ovulation: 50 mg once daily for 5
days starting from 5th day of cycle.
•Also used for male infertility; oligozoospermia.

19. Tamoxifen citrate
•Antagonist action in Breast carcinoma cells, blood
vessels and some peripheral sites (ERα receptors)
•Partial agonist activity on uterus, bone, liver and
pituitary.
•Used in treatment for breast cancer in both pre- and
post-menopausal patients.
•Other use: primary prophylaxis of breast cancer in
high-risk women, as an alternative to clomiphene in
male infertility.
•Dose: 20 mg/day in 1 or 2 doses

20. Other antiestrogen drugs:
•Raloxifene
•Fulvestrant
•Letrozole
•Anastrozole
•Exemestane

21. Progestins
(Progestin = favouring pregnancy)
• Progesterone, the natural progestin is produced in
response to luteinzing hormone(LH) by both females
and males.
• Also synthesized by the adrenal cortex in both sexes.
• Secreted from corpus luteum (10–20 mg/day) in the
later half of menstrual cycle under the influence of LH.
Its production declines a few days before the next
menstrual flow.
• Progestins promote the development of a secretory
endometrium.

23. Progestin actions:
•Uterus: increased secretion
•Cervix: Secretion made viscid favouring sperm penetration
•Vagina: Pregnancy like changes
•Breast: prepares breast for lactation
•CNS: High concentration has sedative effect
•Body Temperature: Slightly rises (0.5o
C)
•Respiration: Stimulates respiration at higher doses
•Metabolism: Prolong use impairs glucose tolerance, raises
LDL and lower HDL, cholesterol levels
•Pituitary: Weak inhibitor of gonadotrophin secretion,
supresses preovulatory LH surge and prevents ovulation if
given during follicular phase

24. MOA: Progesterone binds to Progesterone
Receptor (PR) present in nucleus and undergoes
conformational changes (dimerization) with
Progesterone Response elements (PRE) that
regulates transcription.
Indications:
•As Contraceptive
•Hormone Replacement Therapy (HRT)
•Dysfunctional uterine bleeding
•Endometriosis
•Premenstrual syndrome/tension
•Threatened/habitual abortion
•Endometrial carcinoma

26. Adverse effects:
•General: Breast engorgement, headache, rise in
body temperature, edema, esophageal reflux, acne,
mood swings with higher doses
•Irregular bleeding or amenorrhoea on continuous
administration
•19-nortesterone derivatives: Lowers plasma HDL
levels; promotes atherogenesis
•Impaired glucose tolerance, precipitate diabetes
•Long term administration (HRT): Increase risk of
breast cancer
•Early pregnancy: Masculinization of female foetus
and other congenital abnormality

27. Antiprogestin: Mifepristone
It is 19-norsteroid with potent antiprogestin and significant
antiglucocorticoid, antiandrogenic activity.
MOA: It acts on different phases of mensturation cycle:
•Follicular phase: delay/failure of ovulation
•Secretory/Luteal Phase: blocks progesterone action on
endometrium
•Later stages of cycle: increases Prostaglandin (PG) release
and induces mensturation
•Post implantation: decreases endogenous progesterone,
cervix softens & abortion occurs

29. Mifepristone Indications & Doses:
• Termination of Pregnancy upto 7 weeks, 600mg
single oral dose (+/- 400mg misoprostol after 48
hrs)
• Cervical ripening: Prior to attempting surgical
abortion of induction of labour (600mg oral)
• Post-coital contraception (emergency
contraception) Within 72 hrs of intercourse (600mg
oral)
• Once a month contraceptive
• Induction of Labour: In cases of Intra uterine
foetal death or abnormal foetus
• Cushing Syndrome

30. Adverse effects:
•General: Anorexia, nausea/vomiting, tiredness,
abdominal discomfort, uterine cramps, loose
motions
•When used for termination of pregnancy:
Prolonged bleeding, failed abortion
•When used as postcoital contraceptive:
Subsequent menstrual cycle is disturbed

31. Oral contraceptives
Oralcontraceptives
Oral contraceptives

32. Combined contraceptive pills:Combined contraceptive pills:
•The OCPs with combined estrogen and progesterone are
the most common type of contraceptives.
•MOA: The estrogen provides a negative feedback on the
release of LH and follicle-stimulating hormone (FSH) by the
pituitary gland, thus preventing ovulation. The progestin
also inhibits LH release and thickens the cervical mucus,
thus impeding the transport of sperm.
•These OCPs are started on the 1st day of Menses and
continued for 21 days followed by a 7 days withdrawl
peroid to allow menses.
•Eg: Norgestrel 0. 3 mg + Ethinylestradiol 0.03 mg (21 tab)
and Ferrous fumarate 75 mg (7 tab)

33. Combined pills commonly used in Nepal
•Sunaulo Gulaf: Levonorgestrel 0.15 mg + Ethinylestradiol
0.03 mg + ferrous fumarate75 mg
•Nilocon: Levonorgestrel 0.15 mg + Ethinylestradiol 0.03
mg + ferrous fumarate75 mg

34. Phased Pill
•Phased pills are triphasic regimens that act by mimicking
the normal hormonal pattern in a menstrual cycle.
•The estrogen dose is kept constant while the amount of
progestin is low in the first phase and progressively higher in
the second and third phases.
•Phasic pills are particularly recommended for women over
35 years of age and for those with no withdrawal bleeding.
•Levonorgestrel (50–75 –125 μg) + Ethinylestradiol (30–40 –30 μg)
•Norethindrone (0.5–0.75 –1.0 mg) + Ethinylestradiol (35–35 –35 μg)

35. Progestin only pills ( Mini Pills)
• Contains only progestin and are taken on a
continuous schedule
• Norethindrone 0.35 mg
• Norgestrel 75 ug
• MOA: Progesterone alone can inhibit ovulation
in 40% cycles & thickens cervical mucosa that
impedes sperm penetration.

36. Post coital contraceptive
• Levonorgestrel 0.5 mg + Ethinylestradiol 0.1 mg
• Taken as early as possible but within 72 hrs of
unprotected intercourse and repeated after 12 hrs
• A single dose of Mifepristone 600 mg within 72 hrs of
intercourse
• Levonorgestrel 0.75 mg taken twice with 12 hrs gap
within 72 hrs of intercourse or Levonorgestrel 1.5 mg

37. Implants Contains progestins as:
•Levonorgestrel 216mg (36 mg per rod)
Effective for five years
•Levonorgestrel 150 mg (75 mg per rod)
Effective for three years
•Primarily acts by suppressing GnRH pulse
•Inhibits ovulation

38. INTRAUTERINE DEVICES
•Contains levonorgestrel (LNg20)
Effective for up to seven years
•Acts primarily by producing uterine changes
•Cervical mucus thickening
•Hostile endometrium

39. • Injectable contraceptives obviate the need for
daily ingestion of pills. They are given i.m. as oily
solution & are highly effective.
• Depot medroxyprogesterone acetate (DMPA)
150 mg at 3-month intervals. After i.m. injection
peak blood levels are reached in 3 weeks and
decline with a t½ of ~ 50 days.
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