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

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Merck Serono Israel

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Off-Label Product Use

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   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.

 GnRH agonist-based stimulation:  Global LH supplementation is of no benefit.

 Advantage in LH-suppressed patients.

Lisi et al. 2002 Marrs et al. 2004 100 80 60 40 20 0 LH level [U/L] Days

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

 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

Ganirelix dose finding study

Bad reproductive outcome with 1mg and 2 mg doses

Response to GnRH antagonist: “Bell shape”

“hypo-responders” “hyper-responders”

OPTIMALH: Antagonist – Luveris study

Who needs exogenous LH during ovarian stimulation after administration of a GnRH antagonist?

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?

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

      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.

 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%.

Age (years) BMI (kg/m 2 ) Infertility duration(months) Basal E 2 (pmol/l) Basal P (nmol/l) Basal LH (IU/l) High responders (n=12)

32 (2.5) 20.6 (1.9) 44 (30) 169 (46) 2.7 (0.9) 7.0 (2.6)

Normal responders (n=34)

30 (4)

P

0.17

21.9 (3.2) 32 (19) 0.23

0.11

180 (49) 2.8 (0.9) 5.5 (2.7) 0.51

0.61

0.09

E 2 before antagonist P before antagonist LH before antagonist E 2 24 hours later P 24 hours later LH 24 hours later E 2 increment per oocyte first 24h E 2 trigger day E 2 increment per oocyte total Total FSH dose (units) Endometrial width (mm) High responders (n=12)

2138 (1500) 2.0 (1.3) 4.9 (5.3) 2452 (1755) 2.1 (1.2) 1.34 (0.9) 28 (32) 6571 (3678) 481 (377) 1703 (452) 9.7 (1.7)

Normal responders (n=34)

1749 (736) 2.6 (1.2) 2.2 (0.9) 2384 (1021) 2.7 (0.9) 1.66 (0.78) 68 (49)

P

0.24

0.18

0.005

0.88

0.11

0.25

0.01

5454 (2436) 266 (220) 1597 (467) 9.4( 2.1) 0.25

0.02

0.5

0.66

oocytes Fertilization rate (%) No. embryos obtained No. embryos transferred No. embryos frozen Clinical pregnancy High responders (n=12)

9.7 ) 4.7) 68 (32) 6.7 (4.3) 1.58 (0.79) 5.1 (3.8) 6 (50%)

Normal responders (n=34)

11.6 (7.5)

P

0.4

62 (29) 5.2 (3.5) 2.1 (0.79) 0.54

0.25

0.06

3.3 (3.6) 10 (29%) 0.16

0.204

     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 follicles.

production by the growing

   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.

 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.