1. 1 CONTRACEPTIVE AND PRO-FERTILITY AGENTS Yulia Komarova, Ph.D. ykomarov@uic.edu

2. 2 Control of the Menstrual Cycle

3. 3 Neuroendocrine control of gonadotropin secretion

4. 4 Contraceptives Oral contraceptives: 1. Combination contraceptives – contain both estrogenic and progestogenic agents Monophasic Multiphasic Biphasic Triphasic 2. Progestin-Only contraceptives, “minipill” - continuous use of progestin only Other contraceptives: ORHTO EVRA – transdermal (both estrogenic and progestogenic) NUVARING – hormone-releasing intravaginal ring (both hormones) DMPA – injection of progestin IMPLANON and NORPLANT II- implantable progestin only IUD and MIRENA – insert and an intrauterine device - progestin only

5. 5 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 Contraceptive Agents

6. 6 Triphasic combination tablets Enpresse, Triphasil, Tri-Levlen, Trivora Days 1–6Ethinyl estradiol0.03L-Norgestrel 0.05 Days 7–11Ethinyl estradiol0.04L-Norgestrel 0.075 Days 12–21Ethinyl estradiol0.03L-Norgestrel 0.125 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 0.075 Implantable progestin preparation Implanon... Etonogestrel (one tube of 68 mg)

7. 7 Mechanism of Action Combination contraceptives prevent ovulation selectively suppress FSH and LH secretion and depresses ovarian function; decreases chance of conception and implantation secondary to changes in the cervical mucus and uterine endometrium Progestin-Only Contraceptives prevent ovulation only 60-80% of cycles cause a thickening of cervical mucus and prevent sperm penetration cause endometrial alterations that impair implantation

8. 8 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

9. 9 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)

10. 10 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

11. 11 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

12. 12 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

13. 13 Progesterone Antagonist: Mifepristone and Ulipristal Mifepristone, a "19-norsteroid“, that binds strongly to the progesterone receptor and inhibits the activity of progesterone In the early stage of pregnancy causes detachment of the blastocyst following decrease in hCG and progesterone production, which facilitates expulsion of blastocyst. is used as postcoital contraceptive for termination of early pregnancy with >90% success limited clinical studies suggest that mifepristone may be useful in the treatment of endometriosis, Cushing's syndrome, breast cancer Ulipristal, a derivative of 19-norprogesterone, a partial agonist of the progesterone receptor inhibits LF release and LH-induced follicular rupture, and blocks endometrial implantation of the fertilized egg. remains effective for 5 days after intercourse.

14. 14 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

15. 15 Clomiphene Clomiphene increases the amplitude of LH and FSH pulses without a change in pulse frequency 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 Adverse Effects hot flushes, headache, constipation, allergic skin reactions, and reversible hair loss multiple pregnancy is approximately 10%. Contraindications enlarged ovaries treatment with clomiphene for more than a year may be associated with a risk of low-grade ovarian cancer

16. 16 Other Therapies for Induction of Ovulation Gonadotropins Synthetic GnRH Analogues

17. 17 Gonadotropins Follicle-Stimulating Hormone (FSH) Urofollitropin (uFSH), is a purified preparation of human FSH that is extracted from the urine of postmenopausal women, is used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causes and to treat male infertility. Recombinant forms of FSH (rFSH): follitropin-α and follitropin-β, are used for controlled ovulation hyperstimulation in women, infertility in men due to hypogonadism Luteinizing Hormone (LH) Lutropin-α, the recombinant form of human LH, has only been approved for use in combination with follitropin-α for stimulation of follicular development in infertile women with profound LH deficiency. Human Chorionic Gonadotropin (hCG) Choriogonadotropin -α (rhCG), a recombinant form of hCG, is used for controlled ovulation and hyperstimulation ovarian follicle development in women with hypogonadotropic hypogonadism

18. 18 Ovulation Induction Gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity. Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures. Toxicity & Contraindications the ovarian hyperstimulation syndrome in 0.5–4% and multiple pregnancies in 15–20% cases. the ovarian hyperstimulation syndrome is characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock. headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG.

19. 19 Male Infertility both LH and FSH are used for treatment of infertility in hypogonadal men initial treatment for 8–12 weeks with injections of 1000–2500 IU hCG several times per week following human menopausal gonadotropins (hMG) injection at a dose of 75–150 units three times per week. ln men with hypogonadal hypogonadism, it takes an average of 4–6 months of such treatment for sperm to appear in the ejaculate. an advance that has indirectly benefited gonadotropin treatment of male infertility is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian hyperstimulation of a female partner.

20. 20 Regulation of Gonadotropin Synthesis and Secretion the hypothalamic peptide GnRH is the predominant regulator of gonadotropin synthesis and secretion. GnRH release is pulsatile and is crucial for the proper synthesis and release of the gonadotropins; the continuous administration of GnRH leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes

21. 21 Structures of GnRH and GnRH Analogs AMINO ACID RESIDUE GnRH CONGENER (TRADE NAME) 12345678910 DOSAGE FORMS Agonists GnRH (FACTREL, LUTREPULSE) PyroGluHisTrpSerTyrGlyLeuArgPro Gly-NH 2 IV, SC Goserelin (ZOLADEX) —————D-Ser(tBu)——— AzGly-NH 2 SC implant Nafarelin (SYNAREL) —————D-Nal————IN Triptorelin (TRELSTAR DEPOT, LA) —————D-Trp————IM depot Buserelin* (SUPREFACT) —————D-Ser(tBu)—— Pro- NHEt IN, SC Deslorelin*—————D-Trp—— Pro- NHEt, depot Histrelin (VANTAS, SUPPRELIN LA) —————D-His(Bzl)—— Pro- NHEt SC implant Leuprolide (LUPRON, ELIGARD) —————D-Leu—— Pro- NHEt, depot Antagonists Abarelix* (PLENAXIS) Ac-D-NalD-CpaD-Pal—Tyr(N-Me)D-Asn— (iPr) — D-Ala-NH 2 SC depot Cetrorelix (CETROTIDE) Ac-D-NalD-CpaD-Pal——D-Cit——— D-Ala-NH 2 SC Ganirelix (ANTAGON) Ac-D-NalD-CpaD-Pal——D-hArg(Et) 2 — —D-Ala-NH 2 SC

22. 22 Synthetic GnRH Agonists Gonadorelin is an acetate salt of synthetic human GnRH. Synthetic GnRH analogs: goserelin, histrelin, leuprolide, nafarelin, and triptorelin. These analogs all have D-amino acids at position 6, and all but nafarelin have ethylamide substituted for glycine at position 10. Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin.

23. 23 Therapeutic Uses of Synthetic GnRH Agonists Female and Male Infertility Diagnosis of LH Responsiveness Controlled Ovarian Hyperstimulation pulsatile intravenous administration of gonadorelin every 1–4 hours stimulates FSH and LH secretion. continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. The first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females. The continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids.

24. 24 Synthetic GnRH Receptor Antagonists GnRH antagonists are approved for preventing the LH surge during controlled ovarian hyperstimulation. GnRH antagonists produce an immediate antagonist effect, their use is delayed until day 6–8 of the in vitro fertilization cycle. Ganirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures, they inhibit the secretion of FSH and LH in a dose-dependent manner.

25. 25 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

26. 26 Literature: Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e, Chapter 40. The Gonadal Hormones & Inhibitors Chapter 37 Hypothalamic & Pituitary HormonesHypothalamic & Pituitary Hormones