P-619 Is the algorithm derived, maximum daily dose of 12µg follitropin delta indeed sufficient, even for women considered at risk for underexposure?
Authors: Neumann K , Da Costa Hackstein L I , Eggersmann T K , Depenbusch M , Schultze-Mosgau A , Hiller R A , Griesinger G 
Published: June 2023

Abstract

Study question
Does the follitropin delta (FD) dosing algorithm potentially underexpose high body weight (BW) women, especially those with a low ovarian reserve?

Summary answer
Our data indicate no decrease of ovarian response with increasing BW in women with serum AMH &lt;15pmol/L treated with daily FD 12µg.

What is known already
The FD dosing algorithm stipulates a 1stcycle dose of daily 12µg FD (equivalent to approximately daily 188 IU rFSH) for patients with serum AMH &lt;15pmol/L (2.1ng/ml), irrespective of BW. In trial and real-word study populations (ESTHER-1, 2017; Blockeel, 2022), respectively, nearly 40-50% of patients are thereby exposed to the same 12µg FD dose. In the phase III trial (ESTHER-1), however, only 5% of patients had a BW &gt; 85kg. It has so-far been unclear, if women with high BW, e.g. large volume-of-distribution, are potentially underexposed by the algorithm dose of 12µg daily FD, especially when in the AMH 7-15pmol/L strata.

Study design, size, duration
A single, university center, retrospective analysis of all (n = 337) stimulation cycles with FD treatment performed from 12-June-2016 to 10-Dec-2021. FD was prescribed according to the summary of product characteristics in all patients. BW was assessed in the center on cycle day two or three. Primary outcome is the cumulus-oocyte-complex (COC) number retrieved. A target response is defined as 8-14 COCs, in line with the ESTHER-1 study.

Participants/materials, setting, methods
Women with an indication for IVF or ICSI, treatment naïve (e.g., 1st cycle), undergoing controlled ovarian stimulation in a GnRH-antagonist protocol with hCG or GnRH-agonist triggering for fresh or frozen-thawed transfer. There was no restriction on AMH levels, BW, cycle regularity or presence of PCOS. Data are shown as mean±standard deviation and/or median and range, as appropriate, or proportion.

Main results and the role of chance
Inclusion of 182 first cycles with mean age 33±4.2 years (22-44 years), AMH 25.4±16.7 pmol/L (&lt;0.07-97.86) and BW 72.6±16.3 kg (47-135). 37 out of 182 (20%) women had a BW &gt; 85kg. Median COC number was 7 (0-19) in women with BW &lt; 85kg and 7 (2-20) COCs with BW ≥ 85kg receiving 12µg FD in the AMH &lt;15pmol/L stratum (p &gt; 0.05). A separate comparison by BW strata and AMH strata 0-7 and 7-15 pmol/L, respectively, also indicated no decrease of ovarian response with higher BW. Overall, in all maximally dosed 12 µg cycles (75/182, 41%), a target response was achieved in 32.7% of patient cycles in women with BW &lt; 85kg and 35.7% in women with BW ≥ 85kg.
In patients with AMH ≥15pmol/L, 21/70 patients (30%) had &lt;8 COCs. While no difference in age, BMI, and mean FD dose was observed for those, they were on average taller (1.71±0.06m vs. 1.66±0.06m; p = 0.01), showed a tendency for an increased BW (73kg (48-110kg) vs. 63kg (47-119kg), p = 0.08) and body surface (1.87±0.21 vs. 1.76±0.2m2, p = 0.05) vs. patients with target response. In all subgroups, the prevalence of cycle irregularity was not different between target and hypo- or hyperresponding patients.

Limitations, reasons for caution
The cohort is uncontrolled and the analysis is of retrospective nature. Women with high BW are relatively rare limiting the sample size and power. High BW may be associated with alterations of follicular recruitment and ovarian physiology.

Wider implications of the findings
The maximum FSH dose for low ovarian reserve patients is debated (ESHRE COS guideline 2020). The FD algorithm predicts a maximum response at 12µg FD, e.g. equivalent to only approximately 188 IU FSH/day, in all women with AMH &lt;15pmol/L. Our analysis supports this assumption.

Trial registration number
not applicable