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. Control of the Menstrual Cycle

4. Neuroendocrine Control of Gonadotropin Secretion

5. 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 and NORPLANT II- implantable progestin only • IUD and MIRENA – insert and an intrauterine device - progestin only

6. Oral Contraceptives (OCP’s)

7. Oral Contraceptives (OCP’s)

8. 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

9. 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

10. Pharmacologic Effect of Contraceptive Agents

11. Severe Adverse Effects

12. 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

13. Postcoital Contraceptives

14. 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 • 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.

15. Treatment of Infertility

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 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 • 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

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. • Toxicity & Contraindications • the ovarian hyperstimulation syndrome in 0.5–4%, which is characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock. • multiple pregnancies in15–20% cases. • headache, depression, edema, precocious puberty, and rarely production of antibodies to hCG.

22. 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

23. Structures of GnRH and GnRH Analogs

24. 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.

25. 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.

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 Moy I, Ekpo G. Clomiphene citrate use for ovulation induction: When, why, and how? 2011