Ovarian stimulation in IUI IVF and PCOs with IVF.pptx

Ovulation induction and iui and ivf

1. Optimizing drug usage in ovarian stimulation

2. Learning Objectives Setting the context Role of ovarian stimulation in ART Can we predict ovarian response? Advantages and disadvantages of conventional and mild stimulation protocols. Drugs used for ovarian stimulation Optimising ovarian response-in context of Drugs used In Normal responders GnRH antagonist protocols Luteal phase support In Hyper responders-PCOS group Controlled ovarian stimulation in IUI in PCOS Hyperstimulation for IVF in PCOS Luteal phase support In Poor responders Increasing dose of gonadotropins Short protocol Long GnRH agonist stop protocol Microdose flare up protocol Luteal start of rFSH Others Recent advances- Novel compounds and novel drugs 02

3. Setting the context – ovarian stimulation 03

4. Role of Ovarian Stimulation in ART 04 Integral Step of ART Stimulation of ovaries using a combination of fertility medication Chance of natural conception in anovulatory infertility or One or more oocyte(s) aspirated from the ovarian follicles to be used in ART

5. How to predict ovarian response? 05 Treatment Outcome Predictive factors Clomiphene citrate (CC) Ovulation Amenorrhea, Body mass Index & free androgen index (FAI) Pregnancy Age & oligomenorrhoea FSH Ongoing pregnancy IGF-1, testosterone, age, oligomenorrhea, FAI, duration of infertility CC+ FSH Live birth Age, insulin: glucose, duration of infertility Fauser et al. 2008 Human Reproduction Update; 14(1): 1-14. Appropriate regression models developed that can predict given the specific factors .

6. An example of a predictor scale Imani et al. . Fertil Steril 2002b;77:91 –97 06

7. Stimulation protocols Conventional Shrestha et al. Ann Transl Med. 2015 Jun; 3(10): 137 07 Mild .  2020 May;301(5):1331-1339.

8. Stimulation protocols Conventional Higher number of retrievable oocytes Comparably better pregnancy rates Good predictability of outcome Good expertise with the protocol as it has been used for many years now Shorter duration of stimulation Lower dose of gonadotropins used Recommended for poor responders More tolerable Cost efficient Liu Et al. Arch Gynecol Obstet . 2020 May;301(5):1331-1339. Revelli et al. Reprod Biol Endocrinol 9, 25 (2011). Advantages 07 Mild .  2020 May;301(5):1331-1339.

9. Stimulation protocols Conventional Long protocol – daily injections and/or intra-nasal spraying for longer duration High risk of ovarian hyperstimulation syndrome (OHSS) / multiple gestation Several blood tests & frequent ovarian ultrasounds High rate of Drop-out of IVF program The number of oocyte that could be retrieved is less Not tested in higher age women & prevalence of infertility is increasing with age Revelli et al. Reprod Biol Endocrinol 9, 25 (2011). Human Reproduction, 25 (11) 2678–2684 (2010). Disadvantages 07 Mild .  2020 May;301(5):1331-1339.

10. Drugs used in ovarian stimulation protocols Oral agents Clomiphene citrate Aromatase inhibitors – Letrozole Metformin Natural Gonadotropins & Gonadotropin preparations Human menopausal gonadotropin ( hMG ) Human chorionic gonadotropin ( hCG ) Urinary FSH ( uFSH ) Recombinant FSH ( rFSH ) GnRH antagonists – Cetrorelix Brunton L, Chabner B, Knollman B. Goodman & Gilman’s The Pharmacological basis of Therapeutics. 13 th ed. McGraw Hill medical: 2018

11. Clomiphene Citrate Selective estrogen receptor modulator (SERM) – competitive antagonist of estrogen receptor in hypothalamus and fails estrogens negative feedback effects on the release of GnRH. Uses: infertility due to anovulation. Does not work in primary ovarian or pituitary failure ADR: Hot flushes, weight gain, reversible alopecia, vertigo, polycystic ovaries, depression, mood swings, multiple gestation, rarely OHSS Dose: 50 mg daily for five days, often cycle days 3 to 7 . Can be increased by increments of 50mg (max 150mg/day) in the subsequent cycles. Once ovulation is achieved, the same dose could be continued for four to six cycles High-dose clomiphene citrate (200 to 250 mg daily) may be given for 8 to 10 days in women who are refractory to standard doses. This extended regimen of clomiphene is sometimes used for women who cannot receive exogenous gonadotropins Seli et al. Ovulation induction with clomiphene citrate 2020. WWW.uptodate.com 10

12. Letrozole 22 Aromatase inhibitor – blocks the conversion of testo sterone and androstenedione to estradiol and estrone, respectively thereby reducing negative estrogenic feedback at the pituitary and thus increasing Starting dose is 2.5 mg/day, cycle days 3 to 7, following a spontaneous menses or progestin-induced bleed. If ovulation does not occur, the dose should be increased to 5 mg/day, cycle days 3 to 7, with a maximal dose of 7.5 mg/day Milder side effects – back pain, bone pain, hot flashes, diaphoresis, nausea, night sweats cough, fatigue. Can rarely cause hypersensitivity reaction, blurred vision and hepatitis free of the adverse effects on endometrial and cervical mucus attributed to clomiphene citrate Pritts et al. International Scholarly Research Notices , vol. 2011, Article ID 242864, 4 pages, 2011

13. Metformin 11 1. Johnson NP. Ann Transl Med. 2014 Jun; 2(6): 56 » Biguanide – antidiabetic agent. Insulin sensitizer commonly used in polycystic ovarian disease associated infertility 01 » Most commonly used in clomiphene resistance and is an off-label indication given at a dose of 500mg – 850mg twice a day for 6 months 02 » Side effects include gastrointestinal disturbances, liver dysfunction in infertile women and rarely lactic acidosis. Also aids in modest weight loss 03

14. Dopamine agonists – Bromocriptine & cabergoline Treatment of choice for women with hyperprolactinemia Cabergoline binds more specifically to dopamine D2 receptors on the lactotroph cells – less side effects Bromocriptine – causes nausea but better studied in terms of birth defects Other side effects include vomiting, dizziness, drowsiness, lightheadedness, tiredness, constipation, or headache 1. Fauser et al Overview of ovulation induction . 2020. www.uptodate.com .

15. rFSH – two preparations are available – follitropin alpha & follitropin beta. Can be administered S/C. Absolutely no LH action hMG / uFSH / rFSH – for ovarian follicle development hCG – ovulation trigger Side effects include – polycystic ovaries, multiple gestation, ovarian hyperstimulation, ovarian enlargement, ascites and rarely rupture, hemorrhage and spontaneous abortions uFSH : Obtained from urine and is highly purified. LH is removed by immunodepletion . Very minimal LH action hCG produced by the placenta and secreted in mother’s urine. It is similar in structure and action to LH but more stable than LH. Given IM and rhCG is given SC hMG : It contains FSH + LH activity. Contains other urinary proteins and hence given IM to avoid hypersensitivity reactions. 12 Natural Gonadotropins & Gonadotropin preparations Brunton L, Chabner B, Knollman B. Goodman & Gilman’s The Pharmacological basis of Therapeutics. 13 th ed. McGraw Hill medical: 2018

16. GnRH antagonists – Cetrorelix Competitively block GnRH receptors in the pituitary and inhibit release of LH and FSH Leads to suppression of oestrogen release from ovaries and endogenous LH surge Used in controlled ovarian stimulation During GnRH therapy, antagonists are used to prevent premature LH surge and resulting premature ovulation Lower risk of OHSS and multiple gestation Brunton L, Chabner B, Knollman B. Goodman & Gilman’s The Pharmacological basis of Therapeutics. 13 th ed. McGraw Hill medical: 2018

17. 13 Optimizing ovarian response in normal responders

18. GnRH antagonist protocols Depaloet al. Reproductive Biology and Endocrinology2012,10:26 06 Fixed day 6 protocol: 0.25 mg GnRH antagonist/daily until hCG administration (Albano et al.,F&S 1997) Single dose protocol: 3 mg GnRH antagonist at day 7 of stimulation ( Olivennes et al.,HR 1998) Flexible dose protocol: 0.25 mg GnRH antagonist when follicles reach >14 mm (Diedrich et al., HR 1994)

19. GnRH antagonist flexible protocol 06 Reichman D., Rosenwaks Z. (2014) GnRH Antagonist-Based Protocols for In Vitro Fertilization. In: Rosenwaks Z., Wassarman P. (eds) Human Fertility. Methods in Molecular Biology (Methods and Protocols), vol 1154. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0659-8_13

20. Luteal Phase support in Normal responders To optimize endometrial receptivity – progesterone supplement during luteal phase Initiated on the day of oocyte retrieval or at the time of embryo transfer Given until a positive or negative pregnancy test was obtained or as long as the end of the first trimester IM depot or vaginal preparations more effective than oral Estradiol is commonly administered along with vaginal progesterone to prevent late luteal vaginal bleeding – does not enhance pregnancy rate Paulson et al. In vitro fertilization. 2020. www.uptodate.com

21. 21 Optimizing ovarian response in hyper-responders

22. Overview of management of infertility in PCOS Melo AS. Clinics (Sao Paulo). 2015 Nov; 70(11): 765–769

23. Ovarian stimulation for IUI in PCOS Ovarian stimulation is variably carried out with gonadotropins ( natural or recombinant), clomiphene, letrozole, or combinations thereof. Adjunctive agents such as GnRH agonists and antagonists have also been used occasionally. Ovarian stimulation is followed by ovulation triggering using hCG , which is carefully timed by sonographic and/or hormonal monitoring. Intrauterine insemination generally follows suit within 48 hours of the provision of the ovulatory trigger. McClamrock . Fertility and Sterility® Vol. 97, No. 4, April 2012 0015-0282

24. Hyperstimulation for IVF in PCOS Counselling – increased risk of OHSS & options to minimize risk GnRH antagonist protocol preferred – to reduce the duration of stimulation, total gonadotrophin dose and incidence of OHSS hCG to be used in lowest doses for ovulation trigger Triggering final oocyte maturation & freezing all suitable embryos could be considered in women with PCOS having an IVF/ICSI cycle with a GnRH antagonist protocol - at an increased risk of developing OHSS or where fresh embryo transfer is not planned. International evidence-based guideline for the assessment and management of polycystic ovary syndrome. 2018. URL: monash.edu/medicine/ sphpm / mchri / pcos accessed on 14 Oct 2020

25. Recommendations

26. Trigger type Que. In women with PCOS undergoing GnRH antagonist IVF/ICSI treatment, is the use of hCG trigger or GnRH agonist trigger the most effective for improving fertility outcomes?

27. This question was addressed in a Cochrane review in 2014. In 17 RCTs (n = 1847), in fresh autologous cycles, GnRH-agonists were associated with a lower live birth rate than HCG yet there was also a lower incidence of mild, moderate or severe OHSS than with HCG. In fresh autologous cycles, GnRH-agonists were associated with a lower ongoing pregnancy rate than HCG and a higher early miscarriage rate. However, the effect was dependent on the type of luteal phase support provided. Multiple pregnancy rates were similar. The authors concluded that final oocyte maturation triggering with GnRH-agonist instead of hCG in fresh autologous GnRH-antagonist IVF ± ICSI cycles prevents OHSS to the detriment of the live birth rate . In donor-recipient cycles, use of GnRH agonists instead of hCG resulted in a lower incidence of OHSS, with no evidence of a difference in live birth rate. GnRH agonist as an oocyte maturation trigger could be useful for women who choose to avoid fresh transfers, where donate oocytes are used or in women who wish to freeze their eggs for later use.

28. Group A: GnRHa trigger (n=92)] Group B: hCG trigger (n=101)] Methodology: Prospective observational cohort study. 210 PCOS patients undergoing IVF in an antagonist protocol who were randomized in the previous study (to evaluate if GnRHa trigger is a better alternative than hCG in PCOS patients to prevent OHSS.

29. Results: Embryological and cycle outcomes

30. Results Clinical outcomes FET- Cycle Variables Group A (GnRHa) (n=92) Group B (hCG) (n=101) p-value FET cycles attempted (365) 170 195 - FET cycles cancelled n(%) (21/170) 12.3 (26/195) 13.3 0.776 FET cycles with cleavage/blastocyst transfers     a. cleavage n (%)     b. blastocyst n (%) (46/149) 30.8 (103/149) 69.1 (75/169) 44.3 (94/169) 55.6 0.013 0.013 Mean number of embryos thawed     a. cleavage     b. blastocyst 3.02±0.57 2.15±0.53 3.19±0.48 2.16±0.40 0.079 0.881 Survival rate n (%)     a. cleavage n (%)     b. blastocyst n (%) (123/142) 86.6 (198/221) 89.5 (209/239) 87.4 (181/203) 93.3 0.815 0.894 Mean number of embryos transferred     a. cleavage     b. blastocyst 2.62±0.61 1.92±0.3 2.79±0.41 1.93±0.26 0.068 0.803 Clinical pregnancy/ET n (%) (79/149) 53 (70/169) 41.4 0.039 Implantation rate n (%) (94/321) 29.2 (82/390) 21 0.011 Miscarriage rate n (%) (16/149) 10.73 (20/169) 11.83 0.757 Live birth per ET n (%) (51/149) 34.2 (37/169) 21.89 0.014 Singleton births n (%) (38/79) 48.1 (25/70) 35.7 0.127 Multiple births n (%) (13/79) 16.4 (12/70) 17.1 0.909 Cumulative live birth rate n (%) (51/92) 55.43 (37/101) 36.63 0.009

31. Results Cumulative Live birth rate per patient in FET cycles following GnRHa trigger (blue dotted line) and hCG trigger (red dotted line).

32. 13 Optimizing ovarian response in poor responders

33. Increasing dose of gonadotropins 150 IU vs 300/450 IU: No difference in live birth/ongoing pregnancy rates. Slightly higher number of oocytes retrieved in higher dose 300 IU vs 400/450 IU : No significant difference in ongoing pregnancy rate or number of oocytes retrieved 450 IU vs 600IU: No difference in live birth or number of oocytes retrieved A gonadotropin dose higher than 300 IU is not recommended for predicted poor responders. ESHRE guidelines. 2019

34. Short protocol (Antagonist protocol) Either fixed or flexible protocol as in normal responders L ower gonadotropin consumption and shorter stimulation durations in antagonist cycles Meta-analyses of studies comparing agonist and antagonist protocols by Sunkara et al. (2007) did not show a consistent benefit for any particular pituitary suppression regimen over other protocols in improving outcome measures. Currently available evidence does not favour any particular pituitary suppression regimen for women with poor ovarian response undergoing IVF/ICSI treatment Badawy et al. J Reprod Infertil . 2012 Jul-Sep; 13(3): 124–130

35. Microdose flare-up protocol U tilization of oral contraceptive (OC) priming followed by diluted doses of GnRH agonists,  e.g . leuprolide acetate (LA) 40  µg , given twice daily. Two days later, stimulation is initiated by adding high doses of gonadotropins. Modified flare-up:  high doses of triptorelin (500  µg/day ) for the first 4 days, followed by reduced dose of the medication (to 100  µg/day ) together with the administration of hMG. Ubaldi et al. BioMed Research International, vol. 2014, Article ID 352098

36. Luteal start of GnRH antagonist GnRH antagonist given in the luteal phase of the cycle preceding the ovarian stimulation (3  mg   cetrorelix ) followed by stimulation with rFSH starting on cycle day 2, followed by a flexible GnRH- antgonist protocol (CRASH protocol) M ore follicles, more oocytes and embryos when compared to long protocol Implantation and pregnancy rates increases - approaching the clinical outcome of normal responder patients Badawy et al. J Reprod Infertil . 2012 Jul-Sep; 13(3): 124–130

37. Luteal start of rFSH The antral follicles are present in late follicular phase of the ovarian cycle and initiation of their further development occurs under the action of the premenstrual FSH rise Earlier administraion of FSH might ↑ the number of recruited follicles by opening the recruitment window in the late luteal phase of the preceding cycle Outcome: although ↑ oocyte recovery – did not achieve statistical significance Suikkari et al. Human Reproduction. 2000; 15 (4): 747–751

38. Other protocols (Not commonly used) Short flare-up Ultrashort flare-up Standard flare-up GnRH agonist step-down Single dose depot GnRH agonist Combined GnRH agonist / antagonist Estradiol in the luteal phase Addition of letrozole to the protocol Addition of growth hormone to the protocol Modified natural protocol Addition of androgen to the protocol Badawy et al. J Reprod Infertil . 2012 Jul-Sep; 13(3): 124–130

39. 43 SUMMARY

40. 44 SUMMARY 1 Ovarian stimulation – an integral step of IVF. Involves stimulation of ovaries to produce more oocytes 3 Mild stimulation protocols use low dose Gonadotropins and recommended for poor responders 5 Hyper-responders – main aim to reduces risk of OHSS 1 st line – oral agents 2 nd line – Gonadotropins or ovarian drilling 3 rd line IVF 2 Conventional protocols use high dose gonadotropins. Also more oocyte retrieved. But high risk of OHSS 4 GnRH antagonist protocol is of short duration, produces satisfactory results in both normal and poor responders 6 Luteal phase support with progesterone IM or vaginal preparations produce better outcomes than oral preparations. The role of Estradiol or hCG in addition is not clear