1. Female sex hormones

2. Gonadotropin releasing hormone (GnRH)
Released in “pulsalite manner” from the hypothalamus and acts on Pituitary to stimulate the secretion of gonadotropins-
FSH & LH

3. 1. GnRH analogs A. Short-acting analogs Gonadorelin (t 1/2 = 4 min.)
It can be used in “Pulsatile” manner to stimulate pituitary to secrete FSH and LH.
Uses:
Diagnostic purpose
In infertility: Hypothalamic amenorrhea

4. B. Long-acting analogs
Goserelin, Nafarelin, Leuprolide
After initial stimulation, they will cause suppression of gonadotropin (FSH, LH) secretion. (down-regulation)
Therapeutic Uses:
For Medical castration:
In precocious puberty
Breast Ca
Prostate Ca
Leiomyoma
Endometriosis
Adverse effects:
Gonadal steroidal inhibition in females can cause: Hot flashes, Vaginal atrophy, Decreased bone density

5. 2. GnRH antagonist Ganirelix Cetrorelix
These are pure GnRH antagonists and do not cause initial increase in gonadotropin secretion.

6. 3. Gonadotropins: FSH & LH
Gonadotropin preparations:
Menotropins (LH + FSH)
Recombinant FSH and LH
hCG (Human chorionic gonadotropin)

7. Follicle-Stimulating Hormone (FSH)
Therapeutic uses:
Treatment of infertility caused by hypogonadism in both sexes.
To stimulate ovulation as a part of in-vitro fertilization (IVF) programs.
Side effects:
Hyperstimulation syndrome (enlarged ovaries, ascites, fever, embolism, etc.).
Multiple births.
Gynecomastia in men.

8. Human chorionic gonadotropin (hCG)
It is glycoprotein produced by the placenta
hCG can be used as LH substitute.
Therapeutic uses:
Treatment of infertility both sexes.
In females hCG is used as a part of invitro fertilization (IVF) programs to induce ovulation when mature follicles are present (ovulation occurs 36-40hrs from injection).
HCG injections are used to stimulate the Leydig cells to synthesize testosterone.
Treatment hypogonadism

9. 4. Estrogens Physiological Role:
Development of genital tract and breast.
Secondary sex characters. Menstrual cycle
During follicular phase it cause endometrium to grow
Metabolic effects:
Increase bone mass and prevent bone resorption.
Increase blood glucose.
Increase serum TGs and decrease cholesterol.
Salt and water retention.
Increase blood coagulation and platelet adhesiveness.

10. Types of estrogen Natural estrogens Estradiol Estriol Estrone
Synthetic estrogens
Ethinyl estradiol
Routes of adminstration
Oral IM
Transdermal

11. Uses of Estrogens:
Hormone Replacement therapy:
Primary hypogonadism
Premature ovarian failure; surgical removal of ovaries
Menopause
Oral contraception
Osteoporosis
Atrophic vaginitis

12. Adverse effects
Nausea, vomiting
Thromboembolic problems
Myocardial infarction
Breast Ca
Endometrial Ca
Postmenopausal uterine bleeding
Diethylstilbestrol: Clear cell Ca (cervical & vagina)

13. Prolonged administrations of estrogen  abnormal endometrial hyperplasia, abnormal bleeding patterns, associated with high incidence of endometrial cancer.
This can be prevented by administration of progesterone accompanies the estrogen.
Thus, women taking HRT must also take a progesterone unless they have had a hysterectomy.

14. 5. Selective estrogen receptor modulators (SERMs)
Tamoxifen, Raloxifene
These are drugs that interact with estrogen receptors but have different effects on different tissues.
They can show agonism or antagonism depending upon the tissue type.

15. A. Tamoxifen Antiestrogenic effect: on Breast
Effective in the treatment of breast Ca in patients with tumor cells that are estrogen receptor- positive.
can be given after surgery to eradicate micrometastases
Estrogenic effect: on Endometrium
Can cause endometrial Ca
Not prescribed to treat breast Ca for longer than 3-5 years in non-hysterectomized women

16. Adverse effects:
Nausea/Vomiting
Hot flashes
Vaginal bleeding
Risk of Endometrial Ca
Thromboembolic disorders

17. B. Raloxifene Antiestrogenic effect: Breast, Endometrium
Estrogenic effect: Bones, lipid metabolism
Unlike Tamoxifen, it does not increase the risk of endometrial Ca.
Approved to be used for the prevention of osteoporosis in postmenopausal women

18. 6. Estrogen antagonists Clomiphene (Ovulation inducer):
It blocks estrogen receptors in the hypothalamus and anterior pituitary so reduces negative feedback
↑ FSH and LH secretion leads to ovarian follicle development and ovulation
Side effects include; Multiple pregnancies, Enlarged cystic ovaries.
Used for Inadequate ovulation or low sperm count in males

19. 7. Aromatase inhibitors
Anastrozole : non-steroidal agents; competitive inhibitors
Exemestane : steroidal agent; irreversible inhibitor
Estriol
Estrone
Estradiol

20. Mechanism of action:
Aromatase inhibitors block the synthesis of estrogens from androgen precursors by inhibiting aromatase enzyme.
Uses:
it can be used to inhibit the growth of estrogen-dependent tumors e.g., breast cancer.
Used in postmenopausal women with advanced breast cancer. Unlike tamoxifen, they DO NOT increase the risk of endometrial carcinoma or venous thromboembolism.
Endometriosis

21. 8. Progestins
The physiological role of progesterone is maintenance of pregnancy
Progestins are often combined with estrogen in various formulations to counteract the harmful effects of estrogens (Estrogen can cause endometrial carcinoma)

22. Types Progestins:
Natural progestins:
Progesterone, 17-alpha hydroxyprogesterone
Synthetic progestins:
Medroxyprogesterone (Oral-daily, IM every 1-3 month)
Norgestrel, Levonorgestrel
Norgestimate (less androgenic)
Desogestrel (less androgenic)

23. Uses:
As contraceptive and menopausal hormone therapy
Combined with estrogen (in COCPs & menopausal hormonal therapy)
Progestin only contraceptive preparations
As postcoital contraception
Dysmenorrhea
Dysfunctional uterine bleeding
Endometriosis

24. Adverse effects:
Edema
Depression
Breakthrough bleeding
ADRs of progestins having Androgen-like activity:
Increase the ratio of LDL to HDL cholesterol
Thrombophlebitis
Pulmonary embolism
Acne
Hirsutism
Weight gain
Liver dysfunction

25. 9. Progesterone antagonist
Mifepristone:
Progesterone receptor antagonist
Glucocorticoid receptor antagonist
Therapeutic uses:
Medical termination of pregnancy
(Mifepristone followed 48 hrs later by Misoprostol)

26. 10. Progesterone receptor modulators
Ulipristal  
Mechanism of action:
Progesterone receptor modulators
It inhibit or delay ovulation
Inhibit implantation
Pharmacokinetics
Rapidly absorbed after oral administration
Metabolized by CYP 3A4 to active metabolites
Adverse events
Headache, nausea, abdominal pain, upper abdominal pain, dysmenorrhea, dizziness, and back pain

27. Infertility Clomifene Safest & cheapest , Antiestrogens Gonadotropins
Used in women with hypopituitarism or do not respond to clomifene therapy.
Treatment starts with daily injection of menotrophin (LH = FSH ) or (FSH), followed by 1-2 large doses of chorionic gonadotropin (mostly LH) to induce ovulation.
Adverse Effects: Multiple births, Ovarian hyperstimulation syndrome (OHSS), Bleeding, Low birth weight, Birth defects
In men with hypogonadism, both LH and FSH are given to stimulate spermatogenesis and androgen release.

28. Bromocriptine
Dopamine agonist that inhibits prolactin release
GnRH releasing hormone (Gn-RH) analogs
Aromatase inhibitors
Metformin

29. Drugs affecting uterine smooth muscle
1.Stimulatants of uterus
Include Oxytocin, Ergot alkaloid, Prostaglandins
A. Oxytocin
Enhances uterine contraction
Adverse Effects: Uterine rupture, fetal hypoxia or trauma, hypertension, CVA.
Uses: Post-partum hemorrhage, induce and maintain labor.

30. B. Ergot alkaloid :
Ergometrine, Methylergometrine
Effects:
Contract uterus
Vasoconstriction: Damage vascular endothelial cells at high dose can lead to dry gangrene of the extremities after long term use.
Uses:
Postpartum hemorrhage
To enhance the delivery of the placenta.
Migraine

31. Adverse effects
GI disturbances: diarrhea, nausea, and vomiting prolonged vasospasm
Contraindications
Cerebrovascular diseases; pregnancy

32. C. Prostaglandins
Dinoprostone，(PGE2）
Dinoprost and carboprost (PGF2）
Used in
Medical abortion: combined with mifepristone
Induction of labor
Adverse effects
GI disturbances: nausea, vomiting, Fever and abdominal pain

33. 2. Relaxants of uterus (tocolytics):
Ritodrine, Terbutaline, Salbuterol, Magnesium sulfate, nifedipine
Used to delay Premature birth or preterm labor
Ritodrine
Selective β2 adrenergic receptor agonist that relaxes uterus
Used in preterm labor
Adverse Effects: palpitations, tachycardia

34. Hormonal Contraceptives

35. A. Hormonal Contraceptives
Combined Oral Contraceptive Pills (COCPs)
Contain both estrogen and progesterone
Progestin only preparations
Progestin-only pills (“mini-pill”)
Progestin implants/depot (Levonorgestrel, medroxyprogesterone)
Progestin containing Intrauterine device
Emergency contraception
Postcoital contraception

36. 1. Combined Oral Contraceptive Pills (COCPs)
Mechanism of action:
Estrogen and progesterone causes feedback inhibition of FSH and LH secretion from the pituitary gland to inhibit ovulation.
(main mechanism)
Progestins thicken the cervical mucous and prevent the entry of sperm.
3. Effects on uterine tubes and endometrium decrease the likelihood of fertilization and implantation
Feedback inhibition
↓ LH surge
No Ovulation

37. Adverse effects:
Nausea, vomiting, mastalgia, Breakthrough bleeding
Migraine headache
Wt. gain
Acne and Hirsutism (19-nortestosterone derivatives)
Chloasma (skin pigmentation)
Thromboembolism
Ischemic heart disease
Hypertension
Increase TAG
Cholecystitis and gall stones.
Hepatotoxicity

38. Contraindications:
Absolute contraindications
Thromboembolic, coronary, cerebrovascular disease. Greater risk for :
Women > 35 years of age
Heavy smokers
Obese
Active liver disease
Suspected or overt malignancy of genitals/breast
Undiagnosed vaginal bleeding

39. Relative contraindications:
Hypertension
Migraine
Diabetes mellitus
Uterine leiomyoma
Mental illness
Gall bladder disease
Drug Interactions:
Enzyme inducers (Phenytoin, barbiturates, carbamazapine, Rifampin) cause contraceptive failure
Antibiotics (Tetracyclines, ampicillin, etc.) cause contraceptive failure by suppressing intestinal microflora

40. 2. Progestin-only preparations
Progestin-only pill (“Mini-pill”)
norethindrone or levonorgestrel
Progestin implants/depot
Levonorgestrel: subcutaneous implant, 5 years
Medroxyprogesterone acetate (DMPA): IM, every 3 months.
Progestin containing Intrauterine devices
Progestasert contains progesterone & mirena contains levonorgestrel

41. Uses:
Progestin-only preparations are suitable for women when estrogens are contraindicated :
Smokers
Age > 35 years
H/O cardiovascular disease
Migraine
Liver impairment

42. Disadvantages of progestins:
Frequent spotting
Irregular and unpredictable menstrual cycles
Failure rate is higher as compared to combined COCPs
Unfavorable effect on lipid profile

43. Emergency contraception
Postcoital or “morning after” contraception
Combined oral contraceptive pills: 2 pills within 72 hours of unprotected sexual intercourse and 2 exactly 12 hours later.
Progestin-only pills (Levonorgestrel): one tablet within 72 hours of unprotected sexual intercourse followed by second dose exactly 12 hrs later.
Ulipristal: a selective progesterone receptor modulator; taken within 120 hrs of unprotected sexual intercourse

44. Menopausal hormone therapy (HRT)
Used to treat estrogen deficiency symptoms:
Hot flashes, chills, night sweats, mood swings, insomnia, headache, palpitation
Vaginal and urethral atrophy
Osteoporosis (others drugs are preferred)
Lowest effective dose of estrogen for the shortest duration to relieve estrogen deficiency symptoms in postmenopausal period.

45. Good luck