1. Shahar Kol, Maccabi Health Care Services Rambam Health Care Campus Technion, Israel Institute of Technology

2. Faculty Disclosure No, nothing to disclose X Yes, please specify: Company Name Honoraria / Expenses Consulting/ Advisory Board Funded Research Royalties / Patent Stock Options Equity Position Ownership / Employee Other (please specify) Merck Serono Israelx Off-Label Product Use Will you be presenting or referencing off-label or investigational use of a therapeutic product? XNo Yes, please specify:

3. LH is vital during the follicular phase. GnRH analogs are used to prevent premature LH rise, and untimely ovulation. GnRH analogs attenuate endogenous LH secretion.

4. GnRH agonist-based stimulation: Global LH supplementation is of no benefit. Advantage in LH-suppressed patients. Lisi et al. 2002 Marrs et al. 2004 0 40 20 60 80 100 LH level [U/L] Days

5. GnRH antagonist-based stimulation: Global LH supplementation is of no benefit Konig et al. 2013 0 40 20 60 80 100 LH level [U/L] Days

6. GnRH antagonist-based stimulation: Drop in LH concentration during antagonist treatment is associated with low pregnancy rate, with no relevance to the actual concentrations. Huirne et al. 2005

8. Ganirelix dose finding study Bad reproductive outcome with 1mg and 2 mg doses

9. Response to GnRH antagonist: “Bell shape” “hypo-responders”“hyper-responders”

10. OPTIMALH: Antagonist – Luveris study Who needs exogenous LH during ovarian stimulation after administration of a GnRH antagonist?

11. Objectives What is the proportion of patients that sharply decrease their LH levels following the first GnRH antagonist 0.25 mg administration?  Do these patients benefit from added LH?

12. Definition of GnRH antagonist hyper-responder: <50% pre-antagonist LH level recovery 24 hours later. 0.25 mg 0.5 mg 1.0, 2.0 mg

13.  Ovarian stimulation from day 2 - 3 of cycle.  First Cetrotide dose 4 – 5 days later, following baseline blood test.  24 hours later: another blood test to determine LH recovery.  If recovery is <50% = hyper-responder, add Luveris 150 IU daily until trigger day.  Rest is routine IVF treatment.  Cost: 1 additional blood test.

14.  12 patients out of 46 were defined as “hyper- responders” with a mean LH recovery of 34%.  34 patients – “normal responders” with a mean LH recovery of 75%.

15. High responders (n=12) Normal responders (n=34) P Age (years) 32 (2.5)30 (4)0.17 BMI (kg/m 2 ) 20.6 (1.9)21.9 (3.2)0.23 Infertility duration(months) 44 (30)32 (19)0.11 Basal E 2 (pmol/l) 169 (46)180 (49)0.51 Basal P (nmol/l) 2.7 (0.9)2.8 (0.9)0.61 Basal LH (IU/l) 7.0 (2.6)5.5 (2.7)0.09

16. High responders (n=12) Normal responders (n=34) P E 2 before antagonist2138 (1500)1749 (736)0.24 P before antagonist2.0 (1.3)2.6 (1.2)0.18 LH before antagonist4.9 (5.3)2.2 (0.9)0.005 E 2 24 hours later2452 (1755)2384 (1021)0.88 P 24 hours later2.1 (1.2)2.7 (0.9)0.11 LH 24 hours later1.34 (0.9)1.66 (0.78)0.25 E 2 increment per oocyte first 24h 28 (32)68 (49)0.01 E 2 trigger day6571 (3678)5454 (2436)0.25 E 2 increment per oocyte total 481 (377)266 (220)0.02 Total FSH dose (units)1703 (452)1597 (467)0.5 Endometrial width (mm)9.7 (1.7)9.4( 2.1)0.66

17. High responders (n=12) Normal responders (n=34) P oocytes 9.7 )4.7)11.6 (7.5)0.4 Fertilization rate (%) 68 (32)62 (29)0.54 No. embryos obtained 6.7 (4.3)5.2 (3.5)0.25 No. embryos transferred 1.58 (0.79)2.1 (0.79)0.06 No. embryos frozen 5.1 (3.8)3.3 (3.6)0.16 Clinical pregnancy 6 (50%)10 (29%)0.204

18. It is widely accepted that to secure the best clinical results of assisted reproductive technology, an individualized approach is required. Implication to the LH question: Give to the patient that needs it!  Follicular phase LH physiology: LH levels are more or less constant, allowing for a sufficient supply of androgens, and for a continuous rise in E 2 levels.  We hypothesized that a sharp drop in LH causes a sudden decrease in precursor availability.  The result is insufficient E 2 production by the growing follicles.

19.  In 'long' agonist-based, pituitary down-regulation ovarian stimulation, LH levels are low, but with minimal fluctuations.  in antagonist-based cycles, a sudden antagonist- mediated LH drop leads to depleted E 2 biosynthesis.  the LH-starved system quickly recovers with exogenous LH, resulting in accelerated E 2 production.

20.  About 25% of patients treated with the antagonist protocol hyper-respond, and may benefit from LH supplementation.  High basal LH is associated with hyper response.  This simple approach can shift “individualized treatment” from slogan to practice.