Medications Used with Infertility Treatment

1. Medications Used with Infertility Treatment E.Naghshineh M.D OB& GYN specialist / Infertility fellowship Isfahan university of medical sciences

2. Medications Used with Infertility Treatment • Prescription drugs can be useful when treating infertility issues. These medications are forms of reproductive hormones that stimulate ovaries into producing and releasing eggs. • Clomiphene Citrate / Clomid • Letrozol • Gonadotropins • Human Chorionic Gonadotropin • GnRH Antagonists • GnRH Agonists • Progesterone

3. Clomiphene Citrate / Clomid • Causes release of high amounts of FSH, which initiates growth of ovarian follicles • Taken orally for 5 days during early menstrual cycle (2-5 th day) • Should have an ultrasound prior to using these medications • Most common side effects : mood changes, hot flashes, minor visual disturbances, headaches, irritability and anxiety, vaginal dryness or thinning of endometrial lining

4. Clomiphene Citrate / Clomid • Side effects are temporary and subside once clomid is stopped Ovarian cysts may develop and remain for 4-6 weeks once a woman stops taking clomid, but these cysts are usually harmless • Higher multiple birth rate: 5-10 percent • In most cases: twins • Not been shown to cause the development of birth defects

5. Letrozol (femara) • Clomiphene citrate: drug of first choice for either ovulation induction or superovulation clomiphene citrate lasts for a long time in the body and may therefore have an adverse effect on the cervical mucus and uterine lining • Some patients, such as PCOS do not respond well to clomiphene citrate • Letrozole widely used in women with breast cancer, aromatase inhibitors • Letrozole inhibiting aromatase thereby suppressing estrogen production • Compared with clomiphene citrate, letrozole is associated with a thicker uterine lining and a lower miscarriage rate

6. Letrozole • 2013 meeting of ASRM, results of PPCOS study • Ovulation rate superior with letrozole (61.7%) than clomid (48.3%) • Cumulative live birth rate higher with letrozole (27.5%) than clomid (19.5%) • Live birth benefit was higher in obese women (BMI≥35) • Letrozole was equal or superior to Clomid at all BMI groups • There was no difference in: - Risk for pregnancy loss (letrozole 31.8% vs Clomid 28.2%) - Multiple pregnancy rates (all twins) (letrozole 3.2% vs Clomid 7.4%) - Number of serious adverse events

7. Letrozole and birth defects • A study: ASRM in 2005, 4.7% serious birth defects in letrozole use, in control babies 1.8% . birth defects were 3 times more likely to occur with letrozole. • Novartis sent a letter to fertility physicians stating: “Femara is contraindicated in women with premenopausal endocrine status, in pregnancy and lactation due to potential for maternal and fetal toxicity and fetal malformations”. • The Canadian study: major birth defect rate in letrozole group 1.2% and in Clomid group 3.0% • In United States, labeling of letrozole already warned that it had been associated with birth defects. Novartis has never sought FDA approval to market letrozole as a fertility medication and was clearly concerned about their liability if given in pregnancy.

8. Letrozole • Letrozole is metabolized rapidly in body, not thought to have significant levels in blood or tissues for a prolonged period of time • In PCOS II study: no difference in rate of birth defects between letrozole and Clomid • Letrozoleside effects: -reduce estrogen levels, treatment duration for letrozole is only 5days -Hot flashes, Headaches, Breast tenderness • No increased risk of miscarriage or a decrease in miscarriage risk • Pregnancy Category: D

9. Gonadotropins • Stimulate ovaries to produce multiple eggs • FSH and LH are known as gonadotropins • Commercially produced gonadotropins are derived from two sources: biological or manufactured • Biological products: over 30 years, often referred to as HMG, extracted from the urine of postmenopausal women • Manufactured products: contain only FSH • Both safe and effective

10. Gonadotropins • Manufactured products : administered by SC • Biological products : administered by IM • Purity of manufactured gonadotropins: use lower doses for a shorter duration of time compared to biological products • Side effects: headache, breast pain, OHSS • Manufactured products: fewer injection-site related side effects, such as pain, redness, itching or swelling

11. Commerical names • FSH: Gonal-f, Follistim, Fostimon, Cinnal-f • HMG: Menopur, Menogon, Merional

12. Pergoveris • Contains 2 medications: follitropinalfa (synthetic version of FSH,150 IU) and lutropinalfa (synthetic version of LH, 75 IU) • Contents of a single vial, injected subcutaneously, once daily

13. Elonva • Corifollitropinalfa, 100 or 150 micrograms, pre-filled syringe in 0.5 ml solution for injection • Corifollitropinalfa is a glycoprotein produced in chinese hamster ovary cells by recombinant DNA technology • Elonva is indicated for COH in combination with a GnRH antagonist for development of multiple follicles in women participating in an ART program

14. Elonva • Dose of Elonva is based on weight and age • A single 100-microgram: weigh less than or equal to 60 kg and 36 years of age or younger - A single 150-microgram: weigh more than 60 kg, regardless of age weigh 50 kg or more and older than 36 years of age

15. Elonva • Single SC injection, preferably in abdominal wall, during early follicular phase of menstrual cycle • GnRH antagonist should be started on stimulation day 5-6 depending on ovarian response, i.e. number and size of growing follicles • Seven days after injection with Elonva on stimulation day 1, COS treatment may be continued with daily injections of recombinant FSH until criterion for triggering final oocyte maturation (3 follicles ≥ 17 mm) has been reached • A single injection of 5,000-10,000 IU hCG administered to induce final oocyte maturation

16. Human Chorionic Gonadotropin (hCG) • hCG: a hormone helps to mature eggs and stimulate ovulation, a hormone produced by the placenta after implantation • Two sources: biological or manufactured • Pregnyl, Novarel, Ovidrel • Usual adult dose for ovulation induction: -hCG: 5000 -10,000 units, IM -r-hCG: 250 mcg, SC

17. Ovitrelle • Ovitrelle 250 micrograms/0.5 mL solution for injection in pre-filled syringe • Equivalent to approximately 6,500 IU • Recombinant human chorionic gonadotropin, r-hCG produced in chinese hamster ovary cells by recombinant DNA technology • Maximum dose: 250 micrograms

18. GnRH Antagonists • GnRH is a hormone hypothalamus gland produces that controls pituitary gland’s production and release of LH and FSH. • As part of an infertility treatment regimen, such as IVF, GnRH Antagonist medications block effect of GnRH on pituitary gland, natural ovulation is prevented , allows timing of ovulation to be better predicted and coordinated with procedures such as egg retrieval • Administration: injection SC, once daily during mid to late follicular phase • Side effects: abdominal pain, nausea, headache, vaginal bleeding and injection site reactions (redness or swelling), OHSS

19. Cetrotide • Cetrorelix acetate, a synthetic decapeptide with GnRH antagonistic activity • Cetrotide 0.25 mg is a sterile lyophilized powder intended for SC injection after reconstitution with sterile water for injection • Inhibition of premature LH surges in women undergoing COH • Administered SC, once daily during early to mid follicular phase, on stimulation day 5 or 6 and continued daily until the day of hCG administration

20. Orgalutran • Orgalutran 0.25 mg/0.5 ml solution for injection • Ganirelix , a synthetic decapeptide with high antagonistic activity to GnRH • Prevention of premature LH surges in women undergoing COH for ART • Starting day of orgalutran is depending on ovarian response, number and size of growing follicles and amount of circulating oestradiol • The start of orgalutran may be delayed in absence of follicular growth, although clinical experience is based on starting orgalutran on day 5-6 of stimulation

21. Orgalutran • Orgalutranand FSH should be administered approximately at same time,preparations should not be mixed, different injection sites • Daily continued up to day that sufficient follicles of adequate size • Time between last Orgalutran injection and hCG injection should not exceed 30 hours, as otherwise a premature LH surge may occur • Administered SC, preferably in upper leg,injection site should be varied to prevent lipoatrophy • Very Common side effect: Local skin reaction at site of injection (predominantly redness, with or without swelling)

22. GnRH Agonists • Fertility medicine, treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children • Injections into fat, implants placed into fat, nasal sprays • Side effects: hot flashes, sexual dysfunction, vaginal atrophy, osteoporosis, infertility, diminished sex-specific physical characteristics • The most well-known and widely used GnRH analogue is leuprorelin (brand name Lupron)

23. GnRH Agonists • Suppression of spontaneous ovulation as part of COH, after GnRHagonists induced a state of hypoestrogenism, exogenous FSH given to stimulate ovarian follicle, followed by hCGto trigger oocyte release • GnRH agonists routinely used are: buserelin, leuprorelin, nafarelin, and triptorelin • Final maturation induction after having performed COH in GnRH antagonist cycles • Women of reproductive age, undergo cytotoxic chemotherapy pretreated with GnRH agonists to reduce the risk of oocyte loss and preserve ovarian function

24. GnRH Agonists • Injectables ( daily, monthly, and quarterly), implants (one month to a year), intranassally • Short-acting injection (once per day): buserelin,leuprorelin, triptorelin • Long-acting depot injection or injected pellet (once every one to six months): leuprorelin, triptorelin • Injected implant (once every one to three months): buserelin, goserelin, leuprorelin • Surgically implanted pellet (once per year): histrelin, leuprorelin • Nasal spray (two to three times per day): buserelin, nafarelin

25. Progesterone • Administration: injection and intravaginal gel or suppository • Produced primarily by ovaries, rise sharply shortly after ovulation, preparing inner lining of uterus to receive a fertilized egg • If egg has not been fertilized, ovaries stop producing progesterone and menses begins within 24 to 48 hours • If fertilization occurs, ovaries continue to produce progesterone, which is important in maintaining the pregnancy • Supplemental administration of progesterone: - some women do not produce sufficient progesterone , may have difficulty conceiving - Women undergoing ART procedures

26. Progesterone • Usually started a few days after ovulation and is continued until either menses occurs or pregnancy is confirmed • In pregnancy: progesterone may be continued for 10-12 weeks. By this time, the placenta is producing sufficient amounts of progesterone for the remainder of the pregnancy. • Adverse effects: nausea, constipation, breast enlargement and tenderness, headache, drowsiness, vaginal discharge, joint discomfort and depression, fluid retention • Patients with certain medical conditions such as epilepsy, migraine headaches, asthma and cardiac or renal impairment require close observation

27. Visanne • Dienogest, 2mg Tablet • Helps to reduce pelvic pain experienced by women with endometriosis • Taken by mouth once daily, should be taken at same time every day • Can be started on any day of menstrual cycle • Must be taken continuously without regard to vaginal bleeding, after first pack has been finished next should be started without interruption • Is not intended to be used as birth control

28. Visanne • Some of the symptoms of an allergic reaction may include: shortness of breath, wheezing or difficulty in breathing, swelling of face, lips, tongue or other parts of the body, rash, itching or hives on the skin • Do not take Visanneif have or have had a blood clot in: blood vessels of the legs (DVT), lungs (PTE), heart (heart attack), brain (stroke), other parts of the body. • Do not take Visanneif concerned about an increased risk of blood clot

29. Luteal Phase Support in In Vitro Fertilization • Progesterone supplementation of luteal phase of stimulated IVF cycles leads to higher pregnancy rates and is necessary for optimal results. • Progesterone can be administered orally, vaginally, or through I.M. injection • Oral dosing requires a higher concentration in order to compensate for first-pass liver metabolism. The bioavailability of the orally administered progesterone can be as low as 10% • Oral administration may result in noticeable sedative and anxiolytic effects due to progesterone metabolites that enhance inhibitory neurotransmission by binding to the GABAA receptor complex .

30. Progesterone supplementation • I.M injections of micronized progesterone in oil result in a higher peak and longer lasting plasma concentrations, a daily administration is required due to a rapid metabolism. • I.M injections are difficult to self-administer and are often painful. A common practice is to warm up the oil solution in order to decrease its viscosity in an attempt to reduce pain with injection.

31. Progesterone supplementation • Vaginally delivered progesterone to uterus leading to a higher progesterone concentration in endometrial tissue compared to blood serum • Vaginal progesterone supplementation is equally effective and better tolerated by patients than intramuscular preparations. • Sufficient evidence of efficacy and tolerability to make vaginal supplementation the main route of progesterone support in stimulated IVF cycles exists

32. Progesterone supplementation • There are no agreement on the standard dose of progesterone in luteal phase support. • Once-daily Crinone gel, or twice- or thrice-daily Endometrin, or micronized progesterone 200 mg thrice a day are optimal doses of vaginal progesterone for luteal phase support in IVF. • Patients should have a choice about which preparation to use based on convenience and cost considerations.

33. Timing of starting luteal support • In stimulated IVF/ICSI cycles, steroid production in first week after oocyte retrieval is likely to be well timed and more than sufficient, so the start of exogenous support is not apt to be critical within this window. • Nodifference between the three different times of start of luteal support (start luteal support at hCG day, at egg retrieval day and at day of embryo transfer) • Vaginal supplementation is best started within 24 to 48 hours after oocyte retrieval.

34. Progesterone supplementation • There is no need for serum progesterone level monitoring with vaginal supplementation as little correlation exists between serum levels and local endometrial effects or pregnancy outcomes.

35. Progesterone supplementation • First randomized study to conclude that prolongation of progesterone supplementation in early pregnancy has no influence on miscarriage rate, and thus no effect on delivery rate and progesterone supplementation can safely be withdrawn at time of a positive hCGtest. • It is likely that continued progesterone support in early pregnancy beyond the first positive pregnancy test is of little value for successful outcome; however, there are insufficient data to date to establish the right time for discontinuing support.

36. hCG for luteal phase support • GnRH-antagonist cycles that are triggered with GnRH agonists and that involve fresh embryo transfers should have a modified luteal phase support regimen that includes small doses of hCG or LH preparations in addition to standard progesterone support for optimal outcomes. • one RCT where patients at ovum pick up were randomized to receive luteal support as either progesterone only or hCG only or combination of progesterone and hCGshowed that there were no statistically significant differences with regard to main outcome parameter, clinical ongoing pregnancy rate • The odds ratio of OHSS was more than 3fold higher when hCG was added to luteal phase support regimen, confirming that progesterone alone is a better strategy

37. Estradiol for luteal phase support • Addition of oral estradiol to progesterone supplementation in the luteal phase of IVF cycles does not improve outcomes.

38. GnRH agonist for luteal phase support • Administration of 0.1 mg of GnRH agonist triptorelin on day 6 after ICSI led to a significant improvement of implantation and live birth rates after ICSI. • Increased ongoing pregnancy rate,increased luteal-phase serum hCG, estradiol and progesterone concentrations, possibly by a combination of effects on embryo and corpus luteum. • Conclusion: GnRHagonist addition during the luteal phase significantly increases the probability of live birth rates.

39. Thanks for your attention