1. Fertility/Antifertility Drugs
DR. SHABANA ALI

2. Estrogens &progestin Female Sex hormones Synthesis
Gonads & adrenal glands
Functions
Conception, embryonic maturation & development of primary & 2ndary sexual characteristic during puberty & are used therapeutically

3. Estrogens 2) Synthetic Estrogens 1) Natural Estrogens (human, female)
Steroid in nature
Estradiol (17-β-estradiol, major & most potent)
Estrone (E1)= 1/10 potent
Estriol (E3)= 1/10 potent
2) Synthetic Estrogens
Steroidal = Ethinyl estradiol, mestranol & quinestrol
Non-steroidal= Diethyl stilbestrol & chlorotrianisene,

4. Regulation of Female Sex Hormones
HYPOTHALAMUS
GnRH
ANT. PITUITARY
FSH LH
ESTROGEN PROGESTERONE
OVARY

5. Levels of pituitary & ovarian hormones during menstrual cycle

6. Therapeutic uses of Estrogens
Dysmenorrhea (painful menses)
Primary hypogonadism (estrogen-deficient patients)
Postmenopausal hormone therapy ( hot flushes, muscle cramps, anxiety, over breathing)
Osteoporosis
Contraception
Other uses (intractable dysmenorrhea, hirsutisim & amenorrhea; excessive secretion of androgens by ovary)

7. Adverse Effects of Estrogen
. Impaired glucose tolerance (hyperglycemia) Increase incidence of breast, vaginal and cervical cancer
Nausea & breast tenderness (minimized by dose)
Hyperpigmentation
Migraine headache
Gall bladder disease, cholestasis
Cardiovascular — most concern a. Thromboembolism b. Hypertension

8. Progestins 1) Natural Progestins
Progesterone (humans, i.m. ; ineffective orally)
2) Synthetic Progestins
Medroxyprogesterone acetate
Hydroxyprogesterone acetate (i.m)
Norethindrone tablets
Norgestrel
Desogestrel

9. Therapeutic uses of Progesterone
For Contraception (alone or +estrogen)
Hormonal replacement therapy of postmenopausal women (combination)
Secondary amenorrhea, uterine bleeding disorders, leuteal phase support to treat infertility and premature labour

10. Adverse Effects of Progesterone
1. Nausea, vomiting 2. Headache 3. Fatigue, depression of mood 4. Menstrual irregularities 5. Weight gain (fluid retention) 6. Hirsutism 7. Masculinization (Norethindrone) 8. Ectopic pregnancy 9. Acne and/or oily skin 10. Loss of sex drive (Libido)

11. Drugs or Devices used for prevention of pregnancy
CONTRACEPTIVES
Drugs or Devices used for prevention of pregnancy

12. Various methods of contraceptive
Condoms
(sheath-male & female)
Female sterilization
(surgical blockade of fallopian tubes)
Vasectomy (surgical sealing of vas)
Cap (rubber sheath; females)
Pill (tablet= E+P)
Mini-pill (progesterone only pill; POP)
cont.

13. Long acting Hormonal Methods
Contraceptive implants
(implanted on skin contains hormone)
Mirena
(IUS; T-shaped contains progesterone)
Coil (IUD; hormones)
Contraceptive injections
Contraceptive patch
(sticky patch; hormones)

14. Natural Birth Control Fertility awareness 2. Withdrawal
3. Lactational amenorrhea method
4. Sympto-thermal method
5. Ovulation method
( Mucus method )
6. Calendar method

15. HORMONAL CONTRACEPTIVES
Hormonal contraceptive cause
Reversible suppression of fertility at will
Over 100 million women worldwide use hormonal contraceptives

16. Types of hormonal contraceptive preparations
Oral Parenteral Implanted
a) Combination Injectable skin
(E+P) Medroxyprogesterone Norgestrel
b) Minipill (Progestins) i.m; oily sol Slow release of steroid 
c) Post coital contraception (E or combination)

17. 1) Oral a) Combination pills Estrogen + Progestin MOA
E+P  inhibit ovulation
P  bleeding at end of cycle
E+P  blocks carcinoma
cont.

18. Types of Regimens i) Monophasic combination tablets Method
E (ethinyloestradiol or mestranol)+P (norethisterone or desogestrel; 0.5-1mg)
Most popular & most effective
e.g., Loestrin, Desogen, Brevicon, Ovcon
Method
1 tab daily for 21 consecutive days  gap of 7 days (bleeding)to maintain cycle of 28 days

19. ii) Phased Regimens To keep low total steroid dose
Recommended for Women > 35 y
Constant Estrogen dose (varied slightly; g)
Progestin = low in first phase  in 2nd phase (normal cycle)
Two types
Biphasic
Triphasic

20. a) Biphasic combination Tablets
1st Phase = Days = 1-10 (one set of tablets)
2nd Phase= Days = (conc. of progestin ; 2nd set of tablets)
e.g., Jenest, Ortho-Novum , Necon
b) Triphasic combination tablets
1st Phase = Days = 1-6 (6 days; one set of tablets)
2nd Phase = Days = 7-11 (5 days; 2nd set of tablets)
3rd Phase = Days = (10 days; 3rd set of tablets)
e.g., Ortho-Novum, Tri-Norinyl, Ortho-tri-Cyclen
cont.

21. Method of Triphasic tablets
a) 1st Phase (6 days)
Ethinyl estradiol (30 g) + Norgestrel (50 g)
b) 2nd phase (5 days)
Doses of E +P  (mid cycle)
c) 3rd phase (10 days)
E (dose ); P (dose  )
d) Gap of 7 days
Bleeding occurs

22. Monophasic combination tablets
Estrogen (mg)
Progestin (mg)
Monophasic combination tablets
Loestrin 21 1/20
Ethinyl estradiol
0.02
Norethindrone acetate
1.0
Desogen, Apri, Ortho-Cept
0.03
Desogestrel
0.15
Brevicon, Modicon, Necon 0.5/35
0.035
Norethindrone
0.5
Demulen 1/35
Ethynodiol diacetate
Nelova 1/35 E, Ortho-Novum 1/35
Ovcon 35
0.4
Demulen 1/50
Ethinyl estradlol
0.05
Ethynodiol dlacetate
Ovcon 50
Ovral-28
D,L-Norgestrel
Norinyl 1/50, Ortho-Novum 1/50
Mestranol
Biphasic combination tablets
Jenest-28, Ortho-Novum 10/11, Necon 10/11, Nelova 10/11
Days 1—10
Days 11—21
Norethlndrone

23. Estrogen (mg) Progestin (mg)
Triphaslc combination tablets
Triphasil, Tri-Levlen, Trivora
Days 1—6
Ethinyl estradlol
0.03
L-Norgestrel
0.05
Days 7—11
Ethinyl estradiol
0.04
0.075
Days 12—21
0.125
Ortho-Novum 7/7/7, Necon 7/7/7
Days 1—7
Ethiriyl estradiol
0.035
Norethindrone
0.5
Days 8—14
0.75
Days 15—21
1.0
Ortho-TrI-Cyclen
Norgestimate
0.18
Norgestlmate
0.215
0.25

24. b) Mini pill or progestin only pill (POP)
Progestin (norethisterone, ethynodiol or norgestrel)
Method
Daily without interruption
Indications for POP
When it is desirable to eliminate estrogen:
During breast feeding (estrogen suppress postpartum lactation) Contraindications to estrogen (e.g. hypertension or breast cancer) Smokers more than 35 years old

25. Disadvantages Slightly higher failure rate (efficacy 97%)
Less reliable contraceptive effect
Inconsistent suppression of ovulation
 incidences of Breakthrough bleeding
Should be taken every day, 365 days of the year & at the same time each day even during menstruation
Oral tablets
Name Progestin (mg) Micronor Norethindrone NOR — Norethindrone Ovrette dl- Norgestrel 0.075

26. Timing of 1st dose after intercourse Reported efficacy Within 72hrs
c) Emergency Postcoital Contraception ( morning-after pill ) Indications: When the desirability of avoiding pregnancy is obvious e.g. rape, unsuccessful withdrawal before ejaculation, condom torn during intercourse, exposure to teratogen e.g.,live vaccine,cytotoxic drug.
Regimen
Timing of 1st dose after intercourse
Reported efficacy
100 µg ethinyl estadiol & 0.5 mg levonorgestrel (Yuzpe regimen) given twice, with 12hr between doses(total tab.)
Within 72hrs
75%
High-dose of estrogen (e.g., 50 µg ethinylestradiol daily for 5 days)
Within 72 hrs %
Mifepristone (a single dose of 10, 50 or 600 mg) ±Misoprostol (400 µg)
Within l20 hrs %

27. 2) Parental contraceptive preparation
Intramuscular injection e.g. Medroxyprogesterone acetate 150 mg, i.m every 3 months 3. Implantable progestin preparation e.g. Norplant — L- Norgestrel (6 tubes of 36 mg each; 5 years protection )

28. Pharmacological Effects of Hormonal contraception
A) MOA
Interfere fertility by:
i) Inhibition of ovulation
E= feed back inhibition of FSH inhibit follicles
P = inhibit secretion of LH  inhibit ovulation
ii) Inhibition of implantation
Alteration of endometrium (by alteration of hormones) = inhibit implantation of fertilized ovum cont.

29. iii) Induction of thick & viscid cervical secretion
Progestins=thick & viscid cervical secretion less conductive for passage of sperm
iv) Hypermotility of Fallopian tube & Uterus
Fallopian Hypermotility= rapid passage of ovum to uterus + prevents normal fertilization
Uterus Hypermotility= expelling of fertilized ovum (Postcoital contraception)

30. Chronic use of HC  ovarian function
B) Effects on Ovary
Chronic use of HC  ovarian function
Morphological changes
Follicular development is minimal
Absence of corporal lutea, larger follicles, stromal edema
Smaller size of ovaries
Majority= normal Menstural Cycle
2% = Amenorrhic for several years

31. C) Effect on Uterus Hypertrophy of cervix (prolonged use)
Polyp formation
Thickening of cervical mucus = less copious
 glandular atrophy + less bleeding ( E)
Clinical uses of Contraceptives
As contraceptive
Treatment of endometriosis (E+P)
Severe dysmenorrhea (E alone; suppression of ovulation)

32. Contraindications & Cautions
Thromboembolic phenomenon, cardiovascular & cerebrovascular disorders
Vaginal bleeding (unknown cause)
Avoided in tumor of breast or other E-dependent neoplasm
Avoid in =Liver disease, asthma, eczema, migraine, diabetes, HTN, optic neuritis, or convulsive disorders

33. Factors Limit Effectiveness of Oral Contraceptives
Vomiting and diarrhea
Drugs interfere with absorption
( eg. Ampicillin )
Inducers of hepatic enzymes
( eg. Barbiturates, phenytoin )

34. DRUGS USED TO TREAT INFERTILITY

35. Drugs used to treat Infertility
Drugs  fertility in females by:
Maturation of ovarian follicles (e.g., HMG)
Ovulation induction (e.g. clomiphen; HCG)
Reduction of excessive prolactin level (e.g., bromocriptine)
Control of endometriosis (e.g., GnRH)
E.g., Antiestrogens (clomiphene & tamoxifen), Gonadotropin Releasing Hormone (GnRH; e.g. Leuprolin, goserlin), Human Menopausal Gonadotropin (HMG) & Bromocriptine

36. 1- Antiestrogens a) Clomiphene Citrate
Partial agonist at Estrogen receptor (has mixed agonist and antagonist activity)
Mechanism of fertility promotion
Blocks Estrogen receptors on hypothalamus & pituitary (oppose –ve feed back of E) FSH & LH   stimulation of ovary= promotion of follicular maturation & induce ovulation
Used in treating infertility caused by lack of ovulation

37. Mechanism of action of Clomiphene

38. Conditions
Normal & functioning pituitary & ovary
If follicular maturation but no ovulation =HCG is added to regimen
Success rate: Ovulation = 80% Pregnancy = 40% Method
50 mg/d for 5 days from day 5th of the cycle to 10th
if no response: mg/d for 5 days from day 5th to 10th

39. ADVERSE EFFECTS OF CLOMIPHENE
1. Hot Flushes 2. Gastric upset (nausea and vomiting) 3. Visual disturbances (reversible) 4. Skin rashes 5. Increase nervous tension 6. Depression 7. Fatigue 8. Weight gain 9. Breast tenderness, heavy menses 10. Hair loss (reversible) - occasional 11. Hyper stimulation of the ovaries and high incidence of multiple birth

40. Clomiphene Therapy

41. Tamoxifene
Competitive partial agonist inhibitor of estradiol at estrogen receptors
First selective SERM
Extensively used in palliative treatment of breast cancer in postmenopausal women
Similar & alternative to clomiphene
Non steroidal agent & given orally

42. 2. GONADOTROPIN RELEASING HORMONE (GnRH)
Pulsatile GnRH =stimulate LH & FSH release Sustained non pulsatile GnRH = inhibit LH & FSH release GnRH= decapeptide found in all mammals Synthetic analogues= Leuprolin, goserelin Uses: Induction of ovulation in patients with hypothalamic amenorrhea (GnRH deficient), Cont…..

43. GnRH and agonists, given S. C
GnRH and agonists, given S.C. in a pulsatile (drip) form to stimulate gonadotropin release (1 – 10 µg / 60 – 120 min)
Given continuously, when gonadal suppression is desirable e.g. endometriosis, precocious puberty and advanced breast cancer in women and prostatic cancer in men
Side effects of GnRH agonists:
Hypo-oestrogenism (long term use), Hot flushes, Decreased libido, Osteoporosis

44. 3. Human menopausal gonadotropin (HMG)
Hormonal preparation having LH & FSH activity
Commercially prepared by extraction from postmenopausal urine
Therapeutic uses
1) Female infertility
HMG+HCG=promote follicular maturation & ovulation
Used when gonadotropins from pituitary is insufficient
2) Male infertility (hypogonadotropic hypogonadism, idiopathic male infertility)
Adverse effects: Fever, ovarian enlargement (hyper stimulation), multiple pregnancy (approx. 20%), gynecomestia (occasional )

45. 4) Human Chorionic Gonadotropin (HCG)
Polypeptide hormone produced by placenta
Similar in structure & actions to luteinizing hormone (LH)
Uses (adjunct in treatment of infertility)
a) HCG+HMG
Induce ovulation by stimulating mid cycle LH
surge in infertile females (follicular maturation must be induced by HMG)
b) HCG + Clomiphen
Promote ovulation if clomiphene (alone) is failed
Adverse effects: Headache, edema & gynecomestia (males)

46. 5) Bromocriptine (Parlodel)
Ergot alkaloid
Uses
Correct amenorrhea & infertility (when prolactin is )
Mechanism of fertility promotion
Stimulate DA receptors (in ant pit) inhibition of prolactin  normalization of Menstrual cycle +fertility
Adverse Effects
. Nausea, vomiting, dizziness, orthostatic hypotension, constipation, dry mouth, leg cramps, insomnia, nasal congestion

47. Effect of DA on Prolactin