CONTRACEPTIVE AND PRO-FERTILITY AGENTS

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

2. Control of the Menstrual Cycle

3. Neuroendocrine control of gonadotropin secretion

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. Contraceptive Agents

6. Contraceptive Agents

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. 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. Pharmacologic effect of Contraceptive Agents

10. Severe Adverse Effects

11. 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 Contraindications Relative Contraindications

12. Postcoital Contraceptives

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 postcoitalcontraceptive 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. 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. 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 arisk of low-grade ovarian cancer

16. Other Therapies for Induction of Ovulation Gonadotropins Synthetic GnRHAnalogues

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 hypogonadotropichypogonadism, polycystic ovary syndrome, obesity, and other causes and to treat male infertility. • Recombinant forms of FSH (rFSH): follitropin-αandfollitropin-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-αfor 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 hypogonadotropichypogonadism

18. Ovulation Induction • Gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropichypogonadism, polycystic ovary syndrome, obesity. • Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures. • Toxicity & Contraindications • the ovarian hyperstimulation syndromein 0.5–4% and multiple pregnancies in15–20% 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. Male Infertility • both LH and FSH are used for treatment of infertility in hypogonadalmen • 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. • lnmen with hypogonadalhypogonadism, 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. Regulation of Gonadotropin Synthesis and Secretion • the hypothalamic peptide GnRH is the predominant regulator of gonadotropin synthesis and secretion. • GnRHrelease 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. Structures of GnRH and GnRH Analogs

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. 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. 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. • Ganirelixand cetrorelixare approved for use in controlled ovarian hyperstimulationprocedures, they inhibit the secretion of FSH and LH in a dose-dependent manner.

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