#pharmacology made easy

1. Gonadal Hormones And
Inhibitors
Dr. Maria Qammar

4. Synthetic Estrogens
a. Steroidal:
a) Ethinyl estradiol
b) Quinestrol
c) Mestranol
d) Estradiol Valerate
e) Estradiol Cypionate
b. Non steroidal:
a. Diethylstibestrol
b. Methestrol
c. Dienestrol
d. Chlorotrianisene

12.  Estrogens increase production of certain proteins
from liver e.g. Corticosteroid binding globulin
(CBG), thyroxine binding globulin (TBG),
tyransferrin and fibrinigen.
 Cause mild salt and water retention…edema

13. Effects On Blood Coagulation:
 Enhance coagulability of blood.
 Increase circulating levels of factor II, VII, IX and X and
decreased antithrombin III.
Other Effects:
 Promote sense of well being

14. Estrogens Clinical Uses:
1. Primary Hypogonadism:
 Primary failure of development of ovaries,
premature menupause, menupause or castration.
 Treatment attempts to mimic the physiology of
puberty.
 To stimulate development of secondary sexual
characteristics
 To stimulate optimal growth
 To prevent osteoporosis
 To avoid psychological concequences of delayed
puberty and estrogen defficiency.

15. Estrogens Clinical Uses:
2. Postmenopausal Hormonal Therapy:
 Given to treat or prevent the following
after menupause
 Vasomotor disturbances
 Urogenital atrophy
 Osteoporosis
 Dermatological changes
 Psychological disturbances
 Increased risk CVS effects

16. Estrogens Clinical Uses:
3. Contraception
4. Dysmenorrhea
Cyclic estrogen with progestin therapy benefits by inhibiting
ovulation, as anovulatory cycles are painless.
5. Inhibition of lactation
6. Acne
Estrogen benefit by suppressing androgen production of
ovary by inhibiting gonadotropin release from pituatry.
7. Hirsuitism
8. Dysfunctional uterine bleeding
9. Amenorrhea due to excessive androgen secretion by
ovary
10. Carcinoma of prostate

17. Adverse Effects of Estrogen

18. Estrogen Contraindication:

19. Progestins
 Classification:
 Natural Progestins
 Progesterone
 Synthetic Progestins:
 Progesterone derivatives
 Hydroxyprogesterone caproate
 Medroxyprogesterone acetate
 Megestrol acetate
 17-Ethinyl testosterone derivatives
 Dimethisterone

20.  19-Nortestosterone Derivatives
 Norethindrone
 Norethnodrel
 Ethynodiol
 Levonorgestrel
 Lynestrenol
 Progesterone with less androgenic effects
 Desogestrel
 Norgestimate
 Gestodene

21. Progestins Introduction
 Synthesized by ovary, testis, adrenal cortex and
placenta.
 Mechanism of Action:
 Bind with intracellular receptors and these complexes
then bind with specific portions of DNA ( progestin
response elements, PRE) to cause enhanced DNA
transcription and protein synthesis.
 Progesterone receptors have been demonstrated in
female sex organs, breast, pituitry and CNS.

24. Clinical Uses
 Hormone replacement therapy
 Contraception
 Dysmenorrhea
 Endometriosis
 Relief from menopausal hot flushes
 Dysfunctional uterine bleeding
 Precocious puberty
 Fibrocystic disease of breast
 Added to decrease the risk of endometrial and
ovarian carcinoma

26. Hormonal Contraceptives
1. Combined oral contraceptive
2. Progestin-only contraceptives
3. Postcoital or emergency contraceptives

27. Combined Oral Contraceptives
• The most frequently used agents contain both an
estrogen and a progestin
• Their theoretical efficacy is considered to be 99.9%
• Combination oral contraceptives are generally provided in
21-day packs with an additional 7 pills containing no
active hormone.

28. Combined Oral Contraceptives
 The estrogen in most combined preparation is
ethinyl estradiol
 Progestins are 19-nor compounds that have
varying degrees of androgenic, estrogenic, and
antiestrogenic activities that may be responsible
for some side effects.

29.  Combined OCP’s may be:
 Monophasic: Content of estrogen and progesterone
remain same in all pills.
 Biphasic: Content of progesterone is different in pills
for first 10 days and that for 11-21 days.
 Triphasic: Content of progesterone is gradually
increased. It is lowest in first phase (1-6 days),
moderate in second phase (7-11 days) and further
increased in third phase (12-21 days).

30. Clinical uses
1) Contraception
2) Endometerosis when dysmenorrhoea is the major
symptoms: long term treatment with estrogen and
progestins

31. Mechanism Of Action
1. Estrogen: Inhibits secretion of FSH via negative
feedback on the anterior pituitary, and thus suppresses
development of the ovarian follicle
2. Progestin:
a) Inhibits secretion of LH and thus prevents ovulation
b) Induces viscous mucus that reduces sperm
penetration, decreased motility and secretion of
fallopian tubes and makes endometrium that is not
receptive to implantation.

32. Pharmacological effects:
 Ovary: Ovarian function is depressed.
 Uterus: Stromal diciduation, glandular atrophy
thickening of cervical mucus
 Breast: Slight enlargement of breast and
suppression of lactation
 CNS: Excitability--- estrogen
Hypnotic effect--- progesterone
 CVS: Heart rate, BP and CO increased.
 Endocrine: Inhibits pituitary gonadotropin secretion
 Increase plasma corticosteroid level,
thyroxine level and aldosterone level

33. Pharmacological Effects:
 Blood: Factors II, VII, IX and X increased, serious
thromboembolic phenomenon
 Metabolism: decrease TG, HDL
 Basal insulin level increased
 Skin: Increased skin pigmentation (chloasma), acne

34. Progesterone Only Pills ( Mini pills)
 These contain low dose of progesterone without any
estrogen
 Preferred in women where estrogen is contraindicated
 Smokers
 >35 YEARS OF AGE
 Risk factor of thromboembolism
 Minipills are oral contraceptives of choice for
 Lactating women
 Sickle cell anemia
 Seizure disorders
 Progesterone only pills are given without any break.
 Thickening of cervical mucus is major mechanism of mini
pills.

35. Parenteral Contraceptives:
Name Drug Route Frequency
DMPA Medroxyprogesterone
acetate
i.m Once in three
months
NET-EN Norethindrone
enanthate
i.m Once in 2 months
NORPLANT Levonorgestrel S.C Replaced after 5
years
IMPLANON Etonorgestrel S.C Replaced after 3
years
UNIPLANT Nomegestrol S.C Replaced after 1
year
CAPRANOR Levonorgestrel S.C Disappear after 1
year

36. Postcoital or Emergency Contraceptives
• Used for postcoital contraception (the “morning-
after pill”)
• PLAN-B is two doses of the “minipill” (0.75 mg
levonorgestrel per pill) separated by 12 hours.
• PREVEN is two 2-pill doses of a high-dose oral
contraceptive (0.25mg of levonorgestrel and 0.05
mg of ethinyl estradiol per pill) separated by 12
hours.
• The first dose should be taken within 72 hours
after intercourse and 2nd dose 12hrs later.

37. Conjugated estrogens: 10 mg three times daily for 5
days
Ethinyl estradiol: 2.5 mg twice daily for 5 days
Diethylstilbestrol: 50 mg daily for 5 days
Mifepristone, 600 mg once with misoprostol, 400 mcg
once1
L-Norgestrel: 0.75 mg twice daily for 1 day eg, Plan B
Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (HD
OCP) Two tablets and then two in 12 hours
1Mifepristone given on day 1, misoprostol on day 3.
Postcoital Contraceptives

38. Adverse Effects:
 Nausea, mastalgia, breakthrough bleeding and
edema are related to the amount of estrogen in
preparation.
 Migraine is made worse with the use of OCPs
 Failure of withdrawl bleeding
 Breakthrough bleeding is the most common problem
with the use of progesterone only pills. Chances
decreases with use of biphasic and triphasic pills.
 Weight gain---- Progestins containing androgenic
properties. Desogestrel and Norgestimate causes less
weight gain.
 Acne and hersuitism--- Progestins containing
androgenic properties

39. Adverse Effects
 Risk of venous thromboembolism, myocardial
infarction and stroke is increased with the use of
OCPs because estrogen increases the clotting
factors and decreases the anticlotting factors.
 Cholestatic jaundice, gall bladder disease and
incidence of hepatic adenomas increased
 Chances of breast and cervical carcinoma are
increased and endometrial and ovarian
carcinoma are decreased by OCP use.
Progesterone is responsible for decreasing risk of
these cancers

40. Contraindications
1) The presence or history of thromboembolic
disease, cerebrovascular disease, MI, Coronary
Artery Disease or congenital hyperlipidemia
2) Known or suspected carcinoma of the breast
3) Carcinoma of the female reproductive tract
4) Estrogen-dependent neoplasia
5) Abnormal undiagnosed vaginal bleeding
6) Pregnancy
7) Past or present liver tumors or impaired liver
function
8) Women over 35 years of age who smoke heavily
(e.g., >15 cigarettes/day)

41. Non contraceptive benefits of OCP’s
 Decrease risk of:
 Other _ Ovarian cyst
 B _ Benign breast disease
 E _Ectopic pregnancy
 N _ Neoplasia (Ovarian, endometrial cancer)
 E _ Endometriosis
 F _ Fibroid
 I _ Iron defficiency anemia
 T _ Tension ( Premenstrual tension syndrome)
 S _ Skeletal ( Rheumatoid arthritis, osteoporosis)

42. Selective Estrogen Receptor Modulators
(SERMs)
 Agents that act as estrogen agonists in some tissues
and antagonists in other tissues.
 Agonist action is beneficial in tissues like bone
(decreased resorption) and blood (better lipid
profile), whereas it is deletarious in cervical, breast
( increased risk of carcinoma) and liver
(predisposition to thromboembolism).

43. Seclective Estrogen Receptor Modulators
(SERMs)
 Tamoxifen
 Tormefine
 Raloxifene
 Ormeloxifene
 Clomephine
 Selective estrogen recptor downregulator (SERD)
 Fluvestrant

44. Tamoxifen:
 Mechanism of action:
 Potent estrogen antagonist in breast and blood
vessels.
 Partial agonist action in bone, uterus and liver.
 Uses:
 Treatment of breast carcinoma
 Improvement in bone mass due to anti
resorptive effect
 Improvement in lipid profile

45. Tamoxifen:
 Adverse effect:
 Increase risk of:
 Endometrial carcinoma
 Thromboembolism
 Hot flushes
 Menstrual irregularities
 Depression
 Anorexia
 Dermatitis

46. Ormeloxifene:
 Mechanism of action:
 Estrogen antagonist in breast and uterus
 Use:
 Approved for treatment of dysfunctional uterine bleeding.

47. Clomiphene Citrate:
 Mechanism of action:
 It binds to estrogen receptor and acts as pure
antagonist in all human tissues
 Induces gonadotropin secretion in women by
blocking estrogen feedback inhibition of pituitary.
 The amount of LH/FSH released at each secretory
pulse is increased
 Uses:
 Treatment of an ovulatory infertility by increasing
GnRH release
 Oligozoospermia

48. Clomiphene Citrate:
 Adverse Effects:
 Polycystic ovaries
 Multiple pregnancy
 Hot flushes
 Gastric upset
 Risk of ovarian tumor increased

49. Fluvestrant (Selective estrogen receptor
downregulator, SERD)
 Pure estrogen antagonist
 Used for treatment of metastatic ER positive breast
cancer in post menupausal woman which has
stopped responding to tamoxifen

50. Aromatase Inhibitors
 Stroidal and irreversible
 Letrozole
 Anastrozole
 Nonsteroidal and reversible
 Exemestane

51. Aromatase Inhibitors
 Mechanism of action:
 Androgens are converted to estrogen in the peripheral
tissues with the help of an enzyme aromatase.
 These drugs inhibit the enzyme and decrease the
formation of estrogen.
 USE:
 Treatment of estrogen dependant breast carcinoma
 Tamoxifen resistant breast carcinoma.
 Adverse Effects:
 Bone pain
 Hot flushes
 Thromboembolism

52. Antiprogestin:
 Mifeprostone

53. Mifeprostone:
 Mechanism of action:
 Binds strongly to the progesterone receptor and inhibits the
activity of progesterone.
 Also block glucocorticoid receptor
 The drug has luteolytic properties when given in the midluteal
period.
 Uses:
 Medical termination of pregnancy
 Cervical ripening
 Emergency contraceptive
 Cushing’s syndrome
 Endometriosis
 Breast carcinoma
 Meningioma
 Fibroids

54. Androgens:
 Most potent:
 Testosterone
 Dihydrotestosterone
 Less potent:
 Androstenedione
 Dehydroepiandrostenedione
 Testosterone is converted to DHT by 5-α reductase
and to estradiol by aromatase

55. Actions of androgens:
Actions of DHT Actions of testosterone Actions of both
testosterone and DHT
•Development and
maturation of external
genitalia ( scrotum,
penis, urethra)
•Feedback inhibition of
LH
•Internal genitalia
development
•Increase in mass and
strength of skeletal
muscle and bone
•Epiphysial fusion
•Male behaviour and
changes of puberty
•Spermatogenesis
•Growth and hypertrophy
of prostate in elderly
•Hematopoisis
•Growth of hair follicles
(pubic, axillary and beard
during puberty)
•Loss of scalp hair in
adults
•Activation of sebacious
glands

56. Androgens Uses:
 Long acting derivatives like a testosterone ethantate
(i.m) are indicated for hypogonadal men.
 Reduce breast engorgement during postpartum
period
 Chemotherapy of breast tumors
 Abused by athletes due to their anabolic properties
 Delayed puberty in boys
 Osteoporosis

57. Adverse Effects:
 Hirsuitism, amenorrhea, clitoris enlargement and
deepening of voice
 Increase risk of atherosclerosis
 Use of androgens during pregnancy cause
masculinization of female fetus and under
masculinization of male fetus
 Sodium retention and edema
 Cholestatic jaundice
 Acne, erythrocytosis, gynaecomastia and
azoospermia

58. Danazol:
 Weak androgenic, progesational and glucocorticoid
activity
 Decreases gonadotropin secretion from pituitary by
causing feedback inhibition
 Uses:
 Endometriosis
 Fibrocystic disease of breast
 Angioneurotic edema

59. Danazol:
 Adverse Effects:
 Weight gain
 Edema
 Acne
 Increased hair growth
 Hot flushes
 Loss of libido
 Elevation of hepatic enzymes

60. Anti androgens
 Steroid synthesis inhibitors:
 Ketoconazole
 Abiraterone
 5-α reductase inhibitors:
 Finasteride
 Androgen receptor inhibitors
 Cyproterone acetate
 Flutamide
 Bicalutamide
 Spironolactone

62. Steroid synthesis inhibitors
 Ketoconazole
 Inhibits synthesis of adrenal and gonadal hormones
 increases the estradiol:testosterone ratio and can cause
gynaecomastia
 Use in prostatic carcinoma is limted due to toxicity
 Abiraterone
 Orally active prodrug and act by inhibiting 17- α
hydroxylase and 17-20 lyase.
 Reduces synthesis of cortisol and androgens
 Used for treatment of refractory prostate cancer

63. 5-α reductase inhibitors:
 Inhibit conversion of testosterone to DHT
 Treatment of BPH, male pattern baldness and
hirsuitism by reducing the production of DHT.

64. Cyproterone acetate
 Androgen receptor antagonist
 Marked progestational effect that suppresses the
feedback enhancement of LH and FSH, leading to a
more effective antiandrogen effect.
 Uses:
 Treatment of hirsuitism
 Contraceptive

65. Flutamide
 Potent antiandrogen
 Uses:
 treatment of prostatic carcinoma
 management of excess androgen effect in women.
 Adverse Effects:
 Mild gynecomastia (probably by increasing testicular
estrogen production)
 Mild reversible hepatic toxicity.