Principles of Ovarian Stimulation

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1 Principles of Ovarian Stimulation Dr Genia Rozen Gynaecologist and Fertility Specialist Royal Women s Hospital and Melbourne IVF

2 Learning objectives Why ovarian stimulation Recap physiology Ovarian cycle development of dominant follicle Clomiphene citrate FSH in IUI FSH in IVF Factors in dosage/ aim Influence of antagonist, agonist & OCP Side effects of stimulation : What is normal what is not Under and over stimulation The future DISCLOSURES: NONE

3 Why?

4 Normal oocyte development

5 Types of Ovarian Stimulation 1. Ovulation induction used for ovulation defects, insemination mimic physiological event 1-2 follicles 2. Controlled ovarian stimulation used in IVF/ICSI stimulation of multiple oocytes not physiological

6 Ovulation Induction with Clomiphene Citrate A selective oestrogen receptor modulator: antioestrogen pituitary, breast, endometrium Given early in a menstrual cycle for five days Alteration of negative feedback leads to higher pituitary production of FSH and ovulation Good for ovulatory disorders where there is some oestrogen e.g. PCOS Antioestrogenic effect on uterus/cervix

7 Ovulation Induction with FSH Indications Resistance to oral agents When a woman fails to conceive despite ovulating on clomiphene Side effects IUI Principles: Low dose daily FSH injections Confirm development of a dominant follicle with ultrasound Trigger ovulation

8 Other Drugs used in Ovulation Induction Letrozole Aromatase inhibitor, Category D Aromatase is an enzyme that catalyses the conversion of androgens to estrogens No anti-e2 effects Metformin Insulin sensitizer, Category C Treatment of insulin resistance, androgen excess; may assist with LOW

9 Controlled ovarian stimulation (COS) Aim is to produce multiple follicles Principles of Superovulation 1. FSH stimulation of multiple follicular growth 2. Suppression of premature ovulation with GnRH agonist or antagonist 3. Trigger ovulation 4. Luteal phase support

10 FSH stimulation Stimulation of a cohort of follicles to grow Not physiological Rapidly rising oestradiol ~ pmol/dl/follicle Number of follicles that grow determined by 1. Ovarian reserve 2. Dose of FSH

11 Determining dose of FSH AMH AFC Age Other: past experience, smoker, weight No evidence of increased oocyte retrieval over FSH 300 per day but possible effect on quality

12 AMH as marker of ovarian reserve 20yrs 40yrs pictures courtesy of D Gook, MIVF 2009 Anderson et al 2012

13 FSH products Recombinant FSH (Gonal F, Puregon) Urinary menotropins (Menopur) Long-acting FSH (Elonva) Biosimilars (Bemfola)

14 Prevention of premature LH surge Rapid and large rise in oestradiol triggers release of LH from anterior pituitary: luteinization of follicles and ovulation Premature release of LH needs to be suppressed

15 Suppression of LH surge GnRH analogues Agonists (nafarelin, triptorelin, leuprolide) Antagonists (ganirelix, cetrorelix)

16 Pituitary switch off GnRH agonists (Synarel, Decapeptyl, Lucrin) Initial stimulation of FSH and LH, then down regulation Best commenced either (i) one week before FSH injections in luteal phase, or (ii) whilst taking COCP for greater than ten days GnRH antagonists (Cetrotide, Orgalutran) Immediate effect Can be used when ovulation is at risk

17 Pill Down Regulation: long protocol COC GnRH agonist FSH hcg 2 12 Menses Bleed Oocyte collection

18 Luteal Down Regulation GnRH agonist FSH hcg Prior luteal phase Menses Oocyte collection

19 Flare (short) protocol GnRH agonist FSH hcg Prior luteal phase Menses Oocyte collection

20 GnRH antagonists Direct inhibitory effect upon gonadotrophin secretion GnRH antagonists compete for and occupy pituitary GnRH receptors, preventing native GnRH occupation of receptor sites and therefore action Immediate action, but requires constant supply, delay in repeat dose is critical eg. am start

21 Antagonist protocol FSH GnRH antagonist hcg Prior luteal phase Menses Oocyte collection

22 Advantages of GnRH antagonists Shorter protocol Start antagonist at: follicle size 14 mm = Flexible start OR day 5 or 6 of FSH = Fixed start Lower incidence of OHSS Option to use agonist as a trigger Preferred by patients less side effects, no nasal spray

23 Meta-analysis GnRH antag versus GnRH agonist protocols Wang R, et al. PLoS One. 2017; 12(4) Comparisons of GnRH antagonist protocol versus GnRH agonist long protocol in patients with normal ovarian reserve: A systematic review and meta-analysis Conclusion GnRH-ant protocol substantially decreased the incidence of OHSS without influencing the pregnancy rate and live birth rate compared to GnRH-a long protocol among patients with normal ovarian reserve.

24 Triggering Ovulation LH surge Resumption of meiosis Release of oocytes into follicular fluid Structural remodelling and luteinization hcg is used to trigger ovulation and is given 36 ± 2 hours pre-egg retrieval Recombinant hcg (Ovidrel) Urinary hcg (Pregnyl)

25 GnRH agonist for trigger Associated with significant reduction in OHSS Can only be used in an antagonist cycle Associated with reduced pregnancy rates due to effect on luteal phase Freeze all Do not use if pituitary/hypothalamic disease

26 After oocyte collection Luteal Phase Support Corpora lutea need LH to maintain production of oestrogen and progesterone Because GnRH analogues suppress LH production, may need luteal phase support

27 Drugs used in luteal support Luteal support Progesterone Crinone Progesterone pessaries Endometrin pessaries IM progesterone hcg (Pregnyl)

28 Progesterone Direct effect on endometrium First pass effect with vaginal approach Lower risk of OHSS than hcg IM Progesterone Trend toward benefit from IM progesterone?

29 hcg Easy to use Long half life Encourages ovarian production of progesterone and oestrogen (and other factors?) BUT higher risk OHSS

30 Risk reduction Reduced OHSS Lower doses of FSH Antagonist cycle Agonist trigger Freeze all, cancel fresh transfer Reduced multiple pregnancy Single embryo transfer

31 Gentle stimulation Low dose may reduce oocyte yield High dose Cost impact to patient despite only modest (if any) increase in live birth per OPU Side effects of medications and hyperstimulation Possible increase in aneuploidy

32 Questions remain Is higher ovarian response detrimental? Optimal regimen for poor responders Role of adjuvants Addition of LH

33 Recent additions Agonist trigger and freeze all Dual trigger Random start protocols

34 The future Advanced in vitro maturation (IVM)

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