CONTRACEPTIVE AND PRO-FERTILITY AGENTS

1. CONTRACEPTIVE AND PRO-FERTILITY AGENTS YuliaKomarova, Ph.D. 312-996-1332 ykomarov@uic.edu

2. Knowledge Objectives • Know the methods of contraception • Understand the mechanisms of action and major pharmacological effects of oral contraceptives (OCP’s) • Understand the mechanism of action of postcoitalcontraceptives • Know benefits and adverse effect of contraceptives • Understand the main principles of treatment of the male and female infertility • Know the first-line and second-line pro-fertility agents: clomiphene and exogenous gonadotrophins • Know the major therapeutic uses of synthetic GnRH agonists and antagonists

3. Contraceptives Oral contraceptives: (OCP’s) 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 (etonogestrel) –implantable • IUD and MIRENA – insert and an intrauterine device - progestin only

4. Oral Contraceptives (OCP’s)

5. Oral Contraceptives (OCP’s)

6. 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 • is used if there is a contraindication to estrogen or if the patient is post-partum and breastfeeding (theoretical risk of decreasing milk production) • prevent ovulation only 60-80% of cycles • cause a thickening of cervical mucus and prevent sperm penetration • cause endometrial alterations that impair implantation

7. Benefits of Oral Contraceptives • Reduction of pregnancies • Reductions of menstrual disorders • Reduction of premenopausal/menopausal symptoms • Reduction of reproductive organ neoplasms • Treatment of reproductive disorders (pelvic inflammatory disease & endometriosis) • Reduced incidence of ectopic pregnancies • Other: reduction of acne, anemia, ulcers, rheumatoid arthritis

8. Pharmacologic Effect of Contraceptive Agents

9. Severe Adverse Effects

10. 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

11. Drug Interactions • Drugs that can decrease the effectiveness of combination-type birth control pills: • antibiotics (cephalosporins, chloramphenicol, macrolides, penicillins, tetracyclines, sulfas, rifamycins), • aprepitant (anti-nausea and -vomiting), • bexarotene (T-cell lymphoma), • bosentan (PAH), • dapsone (Dermatitis herpetiformis), • griseofulvin (antifungal), • certain HIV protease inhibitors (amprenavir, nelfinavir, ritonavir, nevirapine), • modafinil (narcolepsy, obstructive sleep apnea, and shift work disorder), • seizure medications (barbiturates, carbamazepine, phenytoin, primidone, topiramate) • Birth control pills may significantly intensify the effects of alcohol.

12. Postcoital Contraceptives

13. Progesterone Antagonist as Contraceptives • 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 • The combination of a single oral dose of 600 mg of mifepristone and a vaginal pessary containing 1 mg of prostaglandin E1 or oral misoprostol can effectively terminate pregnancy in over 95% of patients treated during the first 7 weeks after conception. • Drug Interactions • "blood thinners" such as warfarin and aspirin can increase the risk of bleeding • long-term corticosteroid therapy • drugs affecting liver enzymes such as azoleantifungals, macrolide antibiotics (erythromycin, dexamethasone, rifamycins) • anti-seizure medicines

14. Case Study • A 23-year-old G0 P0 female presents with complaints of irregular cycles since menarche. • She also has noticed an increase in facial hair and acne for many years. • She has a strong family medical history of diabetes. • On examination, she is noted to have a normal blood pressure, pulse, respiratory rate, and temperature. • She is obese with a body mass index of 34. • She is noted to have some hirsutism and acanthosisnigricans. • Her pelvic examination is normal. Her pregnancy test is negative. • Clinical Approach to Polycystic Ovarian Syndrome (PCOS) • Laboratory studies to be considered are TSH, prolactin, lipid profile, glucose-intolerance screening, endometrial biopsy, 17-hydroxyprogesterone. • Testosterone and dehydroepiandrosterone (DHEAS) levels should be assessed when clinical signs of excess androgen stimulation are present.

15. Case Study • Overall treatment goals • Reduce circulating androgen levels • Protect the endometrium from unopposed estrogen and reduce risk of endometrial cancer • Encourage weight loss and healthy lifestyle changes • Induce ovulation when pregnancy is desired • Monitor for the development of diabetes and cardiovascular disease • Treatment with Combination oral contraceptives • to regulate dysfunctional bleeding and limiting unopposed estrogen thus reducing endometrial cancer risk • to suppresses ovarian androgen production • Secondary • Weight loss can reduce both the hyperinsulinemia and hyperandrogenism with as little as 5% weight loss from initial weight. • Insulin-lowering agents such as metformin can be used for reducing the hyperinsulinism • For patients desiring pregnancy, clomiphene citrate while metformin as an adjunct.

16. Pro-fertility Agents: Clomiphene citrate • a selective estrogen receptor modulator • leads to depletion of estrogen receptors at the level of pituitary and hypothalamus interrupting the negative feedback of estrogen • improves GnRH secretion and increase the amplitude of LH and FSH pulses without a change in pulse frequency • LH and FSH in turn drives follicular growth and maturation

17. The Use of Clomiphene • Clomiphene citrate is used for the treatment of ovulation disorders: anovulation or oligo-ovulation (normal basal levels of endogenous estradiol) including women with polycystic ovary syndrome (PCOS), luteal phase deficiency, and in women with unexplained infertility • Dosage: 50 mg daily/5 days per cycle. The dose may be increased to 100 mg. • The compound has no value in patients with ovarian or pituitary failure. • Clomiphene is also used in men to stimulate gonadotropin release and enhance spermatogenesis • Adverse Effects • vasomotor flushes, abdominopelvic discomfort/bloating, headache, nausea and vomiting, prolonged treatment may be associated with a risk of low-grade ovarian cancer • Contraindications • pregnancy, the presence of significant ovarian cysts • Drug Interactions: unknown

18. Second-line Pro-fertility Agents: Aromatase Inhibitors Letrozole or anastrozole are used alone in inducing ovulation. Letrozole results in higher pregnancy rates in PCOS patients as compared to clomiphene and FSH Letrozole doses is 2.5 mg to 7.5 mg for 5 days in the follicular phase

19. Second-line Pro-fertility Agents: Gonadotropins • Gonadotropinsare used to induce ovulation in women with anovulation that is secondary to hypogonadotropichypogonadism, PCOS, obesity. • Follicle-Stimulating Hormone (FSH) • Urofollitropin (uFSH), is a purified human FSH from the urine of postmenopausal women • Recombinant forms of FSH (rFSH): follitropin-αandfollitropin-β • 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 in women with hypogonadotropichypogonadism

20. 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. • In men 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.

21. Ovulation Induction • Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures. • Side Effects • the ovarian hyperstimulation syndrome in 0.5–4% • multiple pregnancies in15–20% cases • headache, depression, edema, precocious puberty, and rarely production of antibodies to hCG. • Contraindications • androgen-dependent tumors, prostate cancer • an enlarged ovary or ovarian cysts, or an enlargement or tumor of the pituitary gland • an active blood clot, brain lesions • unexplained uterine or genital bleeding • pregnancy

22. Synthetic GnRH Agonists • Gonadorelin is an acetate salt of synthetic human GnRH. • 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. • 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. 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 hyperstimulation procedures, they inhibit the secretion of FSH and LH in a dose-dependent manner.

24. Literature: • Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor • Basic & Clinical Pharmacology, 12e, • Chapter 40. The Gonadal Hormones & Inhibitors • Chapter 37 Hypothalamic & Pituitary Hormones • Eugene C. Toy, Benton Baker III, Patti Ross, John Jennings Case Files® Obstetrics and Gynecology, Fourth Edition (LANGE Case Files), 2012. • Moy I, Ekpo G. Clomiphene citrate use for ovulation induction: When, why, and how? 2011.