1. גרימת ביוץ פרופ' אלכס סימון מחלקת נשים ויולדות – עין כרם היחידה להפריה חוץ גופית

2. Infertility: 1 year of unprotected intercourse without pregnancy Primary infertility: no previous pregnancy has occurred Secondary infertility: infertility + prior pregnancy, although not necessary a live birth 90% of couples should conceive after 12 mo. Of unprotected intercourse Definitions

3. Cause of infertility 1. Male factor25- 40% 2. Female factor 40-55% 3. Both female and male factor 10% 4. Unexplained infertility 10%

4. Cause of female factor 1.Ovulation dysfunction 30-40% 2. Tubal or peritoneal factor 30-40% 3. Unexplained infertility 10-15% 4. Miscellaneous causes 10-15%

5. Ovulation Hormonal control

6. Ovulation dysfunction Ovarian Central Hypogonadotrophic Hypogonadism Group I Anovulation PCOD Group II

7. Induction of Ovulation Use of medications to induce the Use of medications to induce the development of ovarian follicles development of ovarian follicles as needed for: as needed for: - Controlled Ovarian Hypestimulation (COH) - Controlled Ovarian Hypestimulation (COH) Group I and Group II Group I and Group II Unexplained infertility Unexplained infertility Age related infertility Age related infertility - In Vitro Fertilization - In Vitro Fertilization

8. Induction of ovulation Clomiphene citrate Exogenous gonadotropins Exogenous GnRH

9. Clomiphene Citrate Induction of ovulation with Clomiphene Citrate Clomiphene citrate first synthesized in 1956 Clomiphene citrate first synthesized in 1956 Approved for clinical use on 1967 Approved for clinical use on 1967 Anovulatory women who use Clomiphene Citrate : Anovulatory women who use Clomiphene Citrate : - 80% ovulation - 70% of ovulated conceive Drug of choice for chronic anovulation – group II

10. Pharmacology of Clomiphene Nonsteroidal triphenylethylene – affinity to E receptor (estrogen agonist and antagonist properties) Main action is as an anti-estrogen (Hypothalamus, Endometrium, Cervical mucous) Estrogenig affect – Hypophysis (Facilitate FSH secretion)

11. CC at the Hypothalamus Competitive inhibitor of E2 Blocks E receptor in hypothalamus. Interfere with receptor recycling GnRH FSH & LH Folliculogenesis Endometrium – Can be thinner Cervical mucous - dysmucorrhea

12. Clomiphene treatment regimen Administer orally (day 5-9) – 50 mg tablets To start - Progestin induced menses Ovulation takes place day 14-16 Startig dose 50 mg tablet daily Spontaneous or induce ovulation by hCG Follow-up by US + Estradiol level

13. Clomiphene treatment regimen

14. Results of Clomiphene treatment Successfully induce ovulation in approximately 80% Overall cycle fecundity is 15% Cumulative pregnancy rates of 70-75% can be expected over 6-9 cycles of treatment

15. Side Effects of Clomiphene Minor side effects are common transient hot flushes 10%, vasomotor symptoms, and mood swing Other mild or less common side effects include: breast tenderness, pelvic pressure or pain, and nausea Visual disturbance (blurred or double vision, scotomata, light sensitivity) are uncommon <2% but reversible

16. Risks of clomiphene treatment Multiple pregnancy :risk increased to 5-8 % Congenital anomalies: no substantial evidence to be increased Miscarriage: no difference Ovarian hyperstimulation syndrome Incidence of borderline serous ovarian tumors but not with any invasive cancers

17. Unlike CC – Gn acts directly on the ovaries. Gonadotropins Indications: Failed CC Hypo Hypo Unexplaine infertility Assisted Reproductive Technology (ART)

18. Exogenous Gonadotropins HMG (Menogon, Menopur) Highly purified uFSH Rec. FSH (Gonal-F, Puregon, Elonva) Rec. LH (Luveris) FSH acts directly on the ovary to induce folliculogenesis LH can be added when needed

19. Better batch-to-batch consistency Better batch-to-batch consistency Steady supply. Steady supply. A purified compound A purified compound Well tolerated (S.C) Well tolerated (S.C) No antibodies formation No antibodies formation Advantages of Recombinant Human Gonadotropins

20. Mode of treatment 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 GNGN US E2 P Adjusted dose US E2 P US E2 P hCG Insemination Intercourse Monofollicular Mild stimulation OHSS Endometrium COH 2-3 follicles

21. Hypogonadotropic Hypogonadism Drug of choice is menotropins contain both FSH and LH LH is also required for normal steroidogenesis, luteinization, and ovulation

22. Failed CC - PCOD Susceptible to OHSS Chronic low dose of GN Monofollicular ovulation Susceptible to OHSS Chronic low dose of GN Monofollicular ovulation

23. Result of exogenous gonadotropin treatment Successfully induce ovulation in almost 100% Hypogonadotropic hypogonadism Cycle fecundity rate 25%, equal or greater than normal fertile women Cumulative pregnancy rate after 6 mo - 90% Clomiphene resistant anovulation and Unexplained infertility Cycle fecundity rate 5-15% Cumulative pregnancy rate after 6 months - 30-60%

24. Risks of gonadotropin treatment Multiple pregnancy Ovarian Hyperstimulation Syndrome (OHSS)

25. Complications of gonadotropin treatment Multiple pregnancy Spontaneous 1% (Twins) Clomiphene induce 5-8% Gonadotropin 15-30% Normal frequency of monozygotic twin 0.3-0.4%, increase 3 fold with exogenous gonadotropin Spontaneous miscarriage - 20-25%, moderately higher than general rate of 15% Clomiphene and gonadotropin no congenital anomalies

26. Summary - - Familiar with strong tool to induce ovulation - - Should be used adequately with proper indications - - The “art of treatment” to prevent complications - - Use the roper combination to reach your goal (CC for group II, Urinary Gn, recombinant, rLH) - - Use in combination with GnRH analogues (agonists and antagonist) for IVF

29. -Is a deca peptide ( ten AA ). -Half life time is 8 min (10 min bursts every 60 min) -By selective A.A or ethylamide substitutions at 6 and/or 10 (Gly) postions. - -  affinity for GnRH receptors (100-200 times). -  1/2 life to 5 hours. GnRH Synthetic Natural

30. Induction of ovulation with exogenous GnRH GnRH therapy ต้องใช้ intravenous catheter for interval of 2-3 wk. or longer pulsatile fashion low risk ต่อการเกิด multiple pregnancy and ovarian hyperstimulation syndrome

31. Pharmacology and physiology of exogenous GnRH treatment GnRH is administer in continuous pulsatile fashion using portable, programmable minipump IV or subcutaneous IV form จะใช้ dose น้อยกว่า, less cost, more physiologic and more effective rapid metabolized และมี terminal half- life 10-40 minutes after IV administration IV form mimic pulsatile hypothalamic GnRH secretion

32. Indication for exogenous GnRH treatment anovulatory infertile women with hypogonadotropic hypogonadism other ovulatory disorder แต่ ประสิทธิภาพไม่ค่อยดี PCOS hyperprolactinemia กรณีที่ให้ dopamine แล้ว fail or can not tolerate

33. Exogenous GnRH treatment regimens most effective when administered intravenously in low doses (2.5-5.0 microgram/pulse) at a constant interval (every 60-90 min) กรณีที่ไม่ตอบสนองอาจจะ response ต่อ higher dose 10-20 microgram เริ่มให้ที่ dose ต่ำๆ ก่อนแล้วค่อยๆเพิ่ม ขนาดยา Primary hypogonadotropic hypogonadism : low dose 2.5 microgram/pulse ก็สามารถ induce ovulation ได้แต่ follicular phase LH concentration may remain lower than normal and luteal phase progesterone concentration are often reduced แต่ค่า ทั้งสองจะกลับมาปกติเมื่อใช้ higher dose 5.0 micrgram/pulse

34. Exogenous GnRH treatment regimens cont. Secondary idiopathic hypogonadotropic hypogonadism เนื่องจากผู้ป่วยกลุ่มนี้จะ sensitive ต่อ GnRH therapy ดังนั้นควรเริ่ม GnRH ด้วย dose ต่ำก่อน PCOS ควร pretreatment with long acting GnRH agonist (daily subcutaneous administration) for 6-8 wks. Immediately before starting pulsatile GnRH treatment

35. หลังจากที่มีการ ovulation แล้วจะต้อง support luteal phase ต่อโดย 1.GnRH therapy can continue at the same or slower pulse frequency every 120-240 min. 2.small dose of hCG : 2,000 IU every 3 days 3.exogenous progesterone

36. Monitoring exogenous GnRH treatment ไม่ต้อง monitor เนื่องจากโอกาสเกิด superovulation น้อย อาจทำเพื่อดู time of ovulation

37. Results of exogenous GnRH treatment Ovulation rate 50-80% Cycle fecundability 10-30% Risk of multiple pregnancy in GnRH induced conception cycle is comparable to that associated with clomiphene treatment (5-8%) 40-75% lower than that associated with exogenous gonadotropin therapy in anovulatory women (15%) incidence of spontaneous miscarriage in exogenous GnRH induced conception cycles is 30 %, miscarriage rate are lowest in hypogonadotropic hypogonadism less than 20% and highest in PCOS >40%

38. Advantages Prevent the possibility of premature LH surges (as a result of  E in response to Gn)  cancealed cycles. Suppression of endogenous basal LH levels  recruitment of a larger cohort of follicles. Decrease LH stimulation of ovarian androgen production (may interfere with follicular development) Allow better timing of oocyte retrival &synchronise follicular growth. GnRHa

39. Routes: - Intranasal. - S.C. (Longer period + need higher doses Gn+ need more luteal support) - Depot (Longer period + need higher doses Gn+ need more luteal support) (Devreken et al,1996).Effect: - Agonistic (flare up) phase  LH & FSH. on continuous administration) - Down regulation (on continuous administration) Within two weeks). GnRHa

40. Chemically it is also a decapeptide with changing the aminoacid sequense at positions 1,2,3,6 and 10. When GnRH antagonist is applied for short period it leads to abortion of LH peak, diminished E2 production and impairment of follicular growth. GnRH Antagonist