Fertility/Antifertility Drugs DR. SHABANA ALI

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

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,

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

Levels of pituitary & ovarian hormones during menstrual cycle

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)

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

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

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

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)

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

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.

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)

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

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

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)

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

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

ii) Phased Regimens To keep low total steroid dose Recommended for Women > 35 y Constant Estrogen dose (varied slightly; 30-40 g) Progestin = low in first phase  in 2nd phase (normal cycle) Two types Biphasic Triphasic

a) Biphasic combination Tablets 1st Phase = Days = 1-10 (one set of tablets) 2nd Phase= Days = 11-21 (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 = 12-21 (10 days; 3rd set of tablets) e.g., Ortho-Novum, Tri-Norinyl, Ortho-tri-Cyclen cont.

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

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

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

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

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 0.35 NOR —---- ----- Norethindrone 0.35 Ovrette ----- dl- Norgestrel 0.075

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 4 tab.) Within 72hrs 75% High-dose of estrogen (e.g., 50 µg ethinylestradiol daily for 5 days) Within 72 hrs 75 - 85% Mifepristone (a single dose of 10, 50 or 600 mg) ±Misoprostol (400 µg) Within l20 hrs 85 - 100%

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 )

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.

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)

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

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)

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

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

DRUGS USED TO TREAT INFERTILITY

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

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

Mechanism of action of Clomiphene

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:- 100 mg/d for 5 days from day 5th to 10th

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

Clomiphene Therapy

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

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…..

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

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 )

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)

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

Effect of DA on Prolactin