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Endo III

Endo III. Dr.Hazar. 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.

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Endo III

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  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 Danazol 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

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

  6. 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

  7. 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

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

  9. Treatment • Endometriosis • Polycystic ovarian Disease • Prostate Cancer • Precocious Puberty • Breast Cancer

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

  11. Types of Gonadorelines analogues

  12. 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

  13. 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

  14. Types of GnRH analogues+uses

  15. Contraceptives

  16. 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

  17. 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 0.02 - 0.035 (second generation) • c. Low dose estrogen with a lesser androgenic progestin (third generation)

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

  19. Monophasic OC

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

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

  22. 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 levonorgestreland 0.05 mg ethinylestradiol(this product includes a pregnancy test kit)

  23. 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

  24. 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).

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

  26. Morning-After • Diethylstilbestrol • Norethindrone • Ethinylestradiol + levonorgestrel • Postcoital IUD contain Cu (best)

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

  28. 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

  29. 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

  30. 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

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

  32. 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

  33. 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 .

  34. 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 .

  35. 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

  36. Infertility

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

  38. 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.

  39. 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.

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

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