1 CONTRACEPTIVE AND PRO-FERTILITY AGENTS Yulia Komarova, Ph.D.

2 Oral Contraceptives Combined – contain both estrogenic and progestogenic agents Monophasic Multiphasic Biphasic Triphasic Continuous use of progestin only “minipill” – Progesterone only New Generation Yasmin – oral - new progestin component Ortho Evra – transdermal Etonogestrel - implantable Nuvaring – hormone-releasing vaginal ring

3 Estrogen (mg)Progestin (mg) Monophasic combination tablets Alesse, Aviane, Lessinea, Levlite Ethinyl estradiol0.02L-Norgestrel 0.1 Levlen, Levora, Nordette, Portia Ethinyl estradiol0.03L-Norgestrel 0.15 Crysella, Lo-Ovral, Low- Ogestrel Ethinyl estradiol0.03Norgestrel0.30 YasminEthinyl estradiol0.03Drospirenone3.0 Brevicon, Modicon, Necon 0.5/35, Nortrel 0.5/35 Ethinyl estradiol0.035Norethindrone1.0 Ortho-Cyclen, SprintecEthinyl estradiol0.035Norgestimate0.25 Necon 1/35, Norinyl 1+, Nortrel 1/35, Ortho-Novum 1/35 Ethinyl estradiol0.035Norethindrone1.0 Ovcon-35Ethinyl estradiol0.035Norethindrone0.4 Demulen 1/50, Zovia 1/50E Ethinyl estradiol0.05Ethynodiol diacetate1.0 Ovcon 50Ethinyl estradiol0.05Norethindrone1.0 Ovral-28Ethinyl estradiol0.05D,L-Norgestrel 0.5 Norinyl 1/50, Ortho- Novum 1/50 Mestranol0.05Norethindrone1.0 Biphasic combination tablets Ortho-Novum 10/11, Necon 10/11 Days 1–10Ethinyl estradiol0.035Norethindrone0.5 Days 11–21Ethinyl estradiol0.035Norethindrone1.0 Oral and Implantable Contraceptive Agents

4 Triphasic combination tablets Enpresse, Triphasil, Tri-Levlen, Trivora Days 1–6Ethinyl estradiol0.03L-Norgestrel 0.05 Days 7–11Ethinyl estradiol0.04L-Norgestrel Days 12–21Ethinyl estradiol0.03L-Norgestrel Ortho-Novum 7/7/7, Necon 7/7/7 Days 1–7Ethinyl estradiol0.035Norethindrone0.5 Days 8–14Ethinyl estradiol0.035Norethindrone0.75 Days 15–21Ethinyl estradiol0.035Norethindrone1.0 Ortho-Tri-Cyclen Days 1–7Ethinyl estradiol0.035Norgestimate0.18 Days 8–14Ethinyl estradiol0.035Norgestimate0.215 Days 15–21Ethinyl estradiol0.035Norgestimate0.25 Daily progestin tablets Nora-BE, Nor-QD, Ortho Micronor, Jolivette, Camila, Errin... Norethindrone0.35 Ovrette... D,L-Norgestrel Implantable progestin preparation Implanon... Etonogestrel (one tube of 68 mg)

5 Benefits of Oral Contraceptives Reduction of Pregnancies Reductions of menstrual disorders Reduction of premenopausal/menopausal symptoms Reduction of reproductive organ neoplasms Reduction of reproductive disorders (Pelvic Inflammatory Disease & endometriosis Reduced incidence of ectopic pregnancies Other: reduction of acne, anemia, ulcers, rheumatoid arthritis

6 Pharmacologic effect of Contraceptive Agents Effects on Endocrine FunctionThe inhibition of pituitary gonadotropin secretion; increase in the plasma concentration of the corticosteroid-binding globulin; Effects on BloodSerious thromboembolic phenomena; an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III; an increase in serum iron and total iron-binding capacity similar to that reported in patients with hepatitis Effects on the LiverSerum haptoglobins produced in the liver are depressed Effects on Lipid Metabolismestrogens increase serum triglycerides and free and esterified cholesterol. Effects on Carbohydrate Metabolismreduction in the rate of absorption of carbohydrates from the gastrointestinal tract; glucose tolerance Effects on the Cardiovascular Systemincreases in cardiac output associated with higher systolic and diastolic blood pressure and heart rate Effects on the Skinincrease pigmentation of the skin (chloasma)

7 Severe Adverse Effects Vascular Disordersthromboembolism; the risk of venous thrombosis or pulmonary embolism increases 3 times; venous thromboembolism appears to be related to the estrogen but not the progestin content of oral contraceptives Myocardial Infarctiona slightly higher risk of myocardial infarction in women who are obese, have a history of preeclampsia or hypertension, or have hyperlipoproteinemia or diabetes. There is a much higher risk in women who smoke. Cerebrovascular Diseasethe risk of stroke is concentrated in women over age 35. Gastrointestinal Disorderscholestatic jaundice; symptomatic gallbladder disease, including cholecystitis and cholangitis; ischemic bowel disease secondary to thrombosis of the celiac and superior and inferior mesenteric arteries and veins Depressionin about 6% of patients Cancerreduced risk of endometrial and ovarian cancer

8 Contraindications Relative Contraindications Clotting disorders Known cancer Hepatic disorders Diabetes - insulin Pregnancy Age older than 35 years and smoker Migraine Hypertension Varicose veins Cardiac/renal dysfunction Diabetes w/o insulin Hepatitis Hypercholesterolemia

9 Postcoital Contraceptives Conjugated estrogens: 10 mg three times daily for 5 days Ethinyl estradiol: 2.5 mg twice daily for 5 days Diethylstilbestrol: 50 mg daily for 5 days Mifepristone: 600 mg once with misoprostol, 400 mcg once 1 L-Norgestrel: 0.75 mg twice daily for 1 day (eg, Plan B 2 ) Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (eg, Ovral, Preven 2 ): Two tablets and then two in 12 hours

10 Pro-fertility agents: Pro-fertility agents: Estrogen Inhibitors and Antagonists tamoxifen, a competitive partial agonist inhibitor of estradiol at the estrogen receptor, is used in the palliative treatment of breast cancer in postmenopausal women and for chemoprevention of breast cancer in high-risk women; may increase the risk of endometrial cancer raloxifene,estrogen agonist-antagonist, is approved for the prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in women with risk factors. clomiphene, partial agonist, is used as an ovulation- inducing agent cyclophenanthrene structure triphenylethylene structure benzothiophene structure triphenylethylene structure

11 Multiple Outcomes of Raloxifene Evaluation (MORE) Double Blind Placebo-Controlled Trial 7705 PMP women aged 31 to 80 Raloxifene 60 mg/d or 120 mg/d or placebo Follow-up for 36 months for efficacy and 40 months for adverse events Increased bone mineral density (BMD) in femoral neck by 2.1% (60 mg) and by 2.4% (120 mg) Increased BMD in spine by 2.6% (60 mg) and by 2.7% (120 mg) Increased risk of venous thromboembolism Conclusions: Raloxifene increases BMD in spine and femoral neck and reduces risk of vertebral fracture – but increases risk of venous thromboembolism

12 Clomiphene Clomiphene is used in the treatment of ovulation disorders in patients who wish to become pregnant. It stimulates ovulation in 70% of women. The compound is of no value in patients with ovarian or pituitary failure. Clomiphene is also used in men to stimulate gonadotropin release and enhance spermatogenesis Clomiphene increases the amplitude of LH and FSH pulses, without a change in pulse frequency, acting largely at the pituitary level to block inhibitory actions of estrofene on gonadotropin release from the gland Adverse Effects hot flushes, occasionally, headache, constipation, allergic skin reactions, and reversible hair loss have been reported multiple pregnancy is approximately 10%. Contraindications special precautions should be observed in patients with enlarged ovaries. treatment with clomiphene for more than a year may be associated with an increased risk of low- grade ovarian cancer

13 Selective Estrogen Receptor Modulators (SERMs)

14 Other Therapies for Induction of Ovulation Gonadotropins: Follicle-stimulating hormone analog: follitropin-α Human chorionic gonadotropin (hCG) Synthetic GnRH Agonists Gonadorelin (short-acting GnRH)

15 Side effects of synthetic fertility drugs headache flushing abdominal discomfort hot flashes, osteoporosis vaginal dryness altered lipid metabolism multiple births emotional lability acne weight gain hirsituism

16 Progesterone Inhibitors and Antagonists Mifepristone, a "19-norsteroid“, that binds strongly to the progesterone receptor and inhibits the activity of progesterone is used as postcoital contraceptive limited clinical studies suggest that mifepristone may be useful in the treatment of endometriosis, Cushing's syndrome, breast cancer Danazol, an isoxazole derivative of ethisterone (17 -ethinyltestosterone) with weak progestational, androgenic, and glucocorticoid activities binds to androgen, progesterone, and glucocorticoid receptors, and to sex hormone-binding and corticosteroid-binding globulins is use in the treatment of endometriosis; it can be given in a dosage of 600 mg/d. The dosage is reduced to 400 mg/d after 1 month and to 200 mg/d in 2 months. About 85% of patients show marked improvement in 3–12 months. is used in the treatment of fibrocystic disease of the breast and hematologic or allergic disorders

17 Literature: Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e,