1. Endo III
Dr.Hazar

2. Objectives
List the drugs and mechanisms used to attenuate the actions of sex hormones.
Gonadotrophines LH and FSH inhibitors
Gonadotrophines releasing hormones LHRH;agonists &antagonists.
Understand the Types ,MOA,S.E ,uses & C.I. of the hormonal contraceptive drugs.
Understand the Types ,MOA,S.E ,uses & C.I. of the fertility drugs.

3. 1.Danazol & danazol analogues
2.Gonadorelines analogues
3.Fertility drugs

4. 1.Danazol & danazol analogues
1.Gonadotropin inhibitor with antiestrogen ,progestational and androgenic properties
2.synthetic version of the male hormone testosterone
3.inhibits the release of FSH and LH by the pituitary gland
4.decreases estrogen levels similar to menopause, stops ovulation
5.shrink abnormal implants

6. Danazol Indications: 1.Endometriosis
2. Mammary dysplasia (fibrocystic breast nodularity)
3. Menorrhagia ;(but not contraception).
4.Gynaecomastia.

7. Danazol
Side effects
androgenic effects (deepening of the voice, abnormal hair growth, reduced breast size, water retention, acne, weight gain ;nearly all gain weight between 8-10 lbs.)
hypoestrogenic reactions (flushing, sweating, vaginal dryness, irritation)
amenorrhea
irregular vaginal bleeding, muscle cramps

8. Danazol analogues 1-Gestrinone is danazol agonist
Ditto action –danazol
Used only in Endometriosis
2-Cetrorelix-LHRH antagonist ↓FSH &LH used in infertility.
3-Ganirelix-ditto

9. 2.Gonadorelines analogues
Continuos use
↓ Gonadotropines Receptors and sensitivity in the Pituitary ; Down regulation
↓ LH,FSH ;estrogen level ↓
No ovulation
↓ endometrium

10. Treatment Endometriosis Polycystic ovarian Disease Prostate Cancer
Precocious Puberty
Breast Cancer

11. 2.Gonadorelines analogues
Pulsatile use
Activation of natural Gonadotropines pituitary Receptors to stimulate release of FSH and LH
Indication
Induction of ovulation invitro fertilization

12. Types of Gonadorelines analogues

13. GnRH Analogues Nafarelin -nasal spray approved in 1990
-200x>potent than natural LHRH
-relieves symptoms and shrinks implant or stops -them from growing
-puts body into menopausal like state
-side effects:
hot flashes; vaginal dryness; lighter, less
frequentor no menstruation; headaches; nasal irritation
-should not be used in women who are pregnant, breast feeding, or have undiagnosed vaginal bleeding

14. Goserelin Made specifically for treatment of endometriosis in 1990
by decreasing the amount of estrogen in the body, the body is induced into a menopausal state
may be administered by a subcutaneous implant which is placed in the abdominal wall

15. Types of GnRH analogues+uses
Endometriosis
Prostate cancer
IVF
Breast cancer
Buserelin +
Nafarelin
Leuprolin
Triptorolin
Goserelin

16. Contraceptives

17. Objectives
1. Understand the mechanisms by which oral contraceptives prevent ovulation.
2. Know the potential adverse effects & containdication of oral contraceptive therapy .
3. Become familiar with the other type of contrceptives
( non oral )
REF
1. Katzung's.
2. Rang & Dale
3. Goodman and Gilman

18. Types of Oral Contraceptives
Types of preparations
1. Combinations - contain an estrogen and a progestin given continuously for three weeks (most widely used).
a. High dose estrogen ≥ 0.05 mg (first generation)
b. Low dose estrogen < 0.05 mg, usually (second generation)
c. Low dose estrogen with a lesser androgenic progestin (third generation)

20. 2.Sequential Products
     a. monophasic
     b. biphasic
     c. triphasic

23. Monophasic OC

25. 3. Minipills-progestin only (block ovulation, slowing GnRH pulse generation  decreased LH surge)
For female with:
Venous thromboembolism , smoker, DM, HT, migrain & lactation.

26. 4. Morning-After Pill (administer within 72 hrs of coitus, continue 2x for 5 days)

27. Emergency contraceptives
drugs used for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure
to be effective these must be taken within 72 hours of intercourse
two products are available:
Plan B: 0.75 mg levonorgestrel
Preven: 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol (this product includes a pregnancy test kit)

29. Mechanism of Action Combination
Inhibition of ovulation via continuous negative feedback on hypothalamic-hypophyseal axis (LH/FSH suppressed, no LH surge)
Progesterone decreases the frequency of GnRH pulses
Changes in the Endometrium
Thickens cervical mucus- difficult sperm penetration
Changes in the Fallopian Tube
Prevent follicular maturation

30. M.O.A Progestins alone
1.There is variable suppression of FSH, LH and ovulation. Menstruation may occur with irregular cycles.
2. Altered endometrial structure may prevent implantation and heavy cervical mucus may prevent sperm penetration.
3. Continuous use lends itself to long-acting preparations - intramuscular, subcutaneous, or intrauterine depots (medroxyprogesterone acetate, levonorgestrel).

31. Names Levonorgestrel , norethindrone, ethynodiol diacetate
Combinations
Estrogens: Ethinyl estradiol ,Mestranol
Progestins : levonorgestrel , Norethindrone
Progestins-only
Levonorgestrel , norethindrone, ethynodiol diacetate

32. Morning-After Diethylstilbestrol Norethindrone
Ethinyl estradiol + levonorgestrel
Postcoital IUD contain Cu (best)

33. Other oral preparations:
Ethinyl estradiol + norethindrone
Ethinyl estradiol + ethynodiol diacetate
Ethinyl estradiol + norethynodrel
Ethinyl estradiol + levonorgestrel

34. Adverse effects Estrogen-related 1.Cardiovcascular Disease
a. Deep vein thrombosis
b. Thromboembolism
Thromboembolic disorders due to effects on clotting factors and platelet aggregation properties; myocardial infarction; stroke

35. Breakthrough bleeding Urinary tract infection Folic acid deficiency
      Nausea, vomiting
Edema (weight gain, breast engorgement) due to salt and water retention
 Headaches, dizziness
Hypertension resulting from salt and water retention and increased hepatic secretion of angiotensinogen
Breakthrough bleeding
Urinary tract infection
 Folic acid deficiency
Increased serum triglycerides
Dysmennorrhea
Ocular changes
Chloasma
Gall bladder disease related to increased cholesterol precipitation due to a decrease in bile flow

36. Decreased glucose tolerance via lowered sensitivity to insulin; possibly related to estrogen-stimulated release of insulin-antagonistic hormones (e.g., GH, T3+4, cortisol).
Carcinogenesis
     a. breast
     b. endometrial
     c. ovarian
     d. cervical
     e. hepatic

37. Progestin-related
Depression - possibly related to increased MAO activity
Headaches
Loss of hair and/or hirsutism, acne-associated with 19-norsteroids
  Yeast infections

38. Contraindications to Oral Contraceptive Use
Current or past history of deep vein thrombosis, stroke, coronary artery disease, or hypertension
Cancer of the breast
Strong family history of the above
Active liver disease
Heavy cigarette smoking Stroke - smokers over 35

40. Types of non oral contrceptives
1.Barrier-condom
2.Devices-IUD – (levonorgestrel,Cu),Cap.
3.Spermicidal-Nonoxinol (creams and gels).
4.Injections
Monthly injectable – medroxyprogesterone1/12
Norethisterone 8/52
5.Vaginal ring - ethinyl estradiol + etonorgestrel
6.Patch - ethinyl estradiol + norelgestromin
7. Levonorgestrel implants .

41. Levonorgestrel Intrauterine Device
Releases 20 µg levonorgestrel each day
Indicated for contraception
80%–90% reduction in menstrual blood loss (not associated with copper-T IUD)
Also effective in treating menorrhagia, endometriosis
Use up to 5 years
Side effects: breakthrough bleeding, ovarian cysts, acne
Cost effective
Talking Points
Initially, the cost of Mirena® is high, but it becomes cost-effective with extended use.
In contrast to Mirena®, use of the copper-T IUD (Paragard®) is not associated with a decrease in bleeding. However, Paragard® is the only nonhormonal continuous-use method that does not interrupt the menstrual cycle.
Sources
Hubacher D, Grimes DA. Noncontraceptive health benefits of intrauterine devices: a systematic review. Obstet Gynecol Surv. 2002;57:
Kaunitz AM. Beyond the pill: new data and options in hormonal and intrauterine contraception. Am J Obstet Gynecol. 2005;192:
Prescribing information available at:
Prescribing information available at: .

42. Levonorgestrel-releasing intra uterine system
Progesterone releasing IUD
Superior to oral progesterones reduces MBL by 96%
64% women cancelled hysterectomy compared to 14% on
medical treatment, effective contraceptive
Suppresses development of endometrium but does not
suppress ovulation
Effective for 5 years
90% women menorrhagia cured in 3 months

46. Infertility

47. Ovulatory Dysfunction
Causes of ovulatory dysfunction:
polycystic ovary syndrome
hypothalamic anovulation
hyperprolactinemia
premature and age-related ovarian failure
luteal phase defect

48. Polycystic Ovarian Syndrome
Oligomenorrhea/amenorrhea and hyperandrogenism
Prevalence: 5%. Among women with O.D., 70% have PCOS.
Clinical evidence: hirsutism, acne, obesity
Lab evidence: elevated testosterone, elevated DHEA-S.

49. PCOS: Treatment Approach
Weight loss if BMI>30
Clomiphene to induce ovulation
If DHEA-S >2, clomiphene + glucocorticoid (dexamethasone)
If clomiphene alone unsuccessful, try metformin + clomiphene.

50. Endometriosis Medical Treatments
Oral Contraceptives
Progestins
Danazol D.O.C
NSAIDs
GnRH analogues