COMMENTARY

The Benefits of Individualizing Ovarian Stimulation for IVF

Peter Kovacs, MD, PhD

Disclosures

May 31, 2017

Individualized Versus Conventional Ovarian Stimulation for In Vitro Fertilization: A Multicenter, Randomized, Controlled, Assessor-Blinded, Phase 3 Noninferiority Trial

Nyboe Andersen A, Nelson SM, Fauser BC, García-Velasco JA, Klein BM, Arce JC; ESTHER-1 Study Group
Fertil Steril. 2017;107:387-396

Background

Controlled ovarian stimulation is a critical part of in vitro fertilization (IVF), because it recruits sufficient numbers of good-quality oocytes for laboratory procedures. Stimulation is mainly achieved with gonadotropins. The stimulation protocol and medications used for stimulation are individually determined.

The aim of stimulation is to induce simultaneous multifollicular development that will result in the retrieval of 10-15 oocytes.[1] Drug dose is typically determined on the basis of ovarian reserve markers, age, weight, ultrasound findings, and previous response to stimulation.[2,3] Despite careful consideration, there are cases in which too few follicles are recruited, and there are cycles in which the patient hyperresponds. This suggests that the variables on which current dosing is based are imperfect.

Study Summary

This randomized controlled trial compared follitropin delta, a novel recombinant follicle-stimulating hormone dosed on the basis of weight and anti-Müllerian hormone (AMH) (the most reliable ovarian reserve marker), with conventional follitropin alfa for ovarian stimulation in women undergoing IVF.

The researchers compared clinical outcome and response to stimulation with follitropin delta and follitropin alfa. The optimal number of retrieved oocytes was considered to be eight to 14. Providers were blinded to treatment assignment; whereas the dose of follitropin alfa could be adjusted on the basis of response after the first 5 days, the dose was not changed for patients assigned to the follitropin delta group.

In the study, 1329 women underwent randomization and 1326 took at least one dose of the drug. Baseline characteristics were well-matched between the groups. The following findings were obtained:

  1. Ongoing pregnancy rates (30.7% vs 31.6%) and ongoing implantation rates (35.2% vs 35.8%), as well as live birth rates, did not differ between the follitropin delta and follitropin alfa groups.

  2. The number of oocytes collected was similar in both groups. The number of oocytes increased in a linear fashion with AMH levels in the conventional stimulation group, whereas it remained fairly homogenous in the range of eight to 14 with individualized dosing.

  3. Dose adjustment (increase or decrease) was requested in one third of patients in both groups, but actual adjustment was allowed only in the conventional dosing group. Despite this, significantly fewer patients in the individualized dosing group had poor or excessive response.

  4. In patients at risk for hyperstimulation, measures could be taken for prevention (gonadotropin-releasing hormone agonist trigger or elective cryopreservation). Such measures were significantly fewer in the individualized dosing group.

The authors concluded that IVF results with stimulation using AMH- and weight-driven individualized dosing of follitropin delta was clinically not inferior to conventional dosing of follitropin alfa. Response was more often in the optimal range, with less need for ovarian hyperstimulation preventive measures.

Viewpoint

Ovarian reserve testing is part of the infertility evaluation. Various hormonal, ultrasound, and dynamic tests can be used for it.[2] The information is used for counseling, mainly to determine drug dose and protocol for stimulation.[4]

Stimulation has to be individualized to avoid both hyporesponse and hyperresponse. For patients aged 35 years or younger, 150 IU of gonadotropins typically is recommended. The dose is increased by 75 IU for those 36-40 years of age and by another 75 IU for those older than 40 years.[5] This is, however, a general approach, and if all patients received these amounts, not all would end up with an ideal response. In fact, a change from the starting dose was requested by the provider in about one third of the patients in this study.

There are proposed formulas in which the starting dose is determined on the basis of several patient-related variables.[6,7] These work better than the "same dose for everyone" rule, but have not been prospectively validated.

This is the first study in which the drug dose was determined by weight and a biomarker, AMH. The dose was not changed throughout treatment, and the response to stimulation outperformed the conventional approach. It obviously needs to be seen whether this approach will be beneficial for patients with different characteristics (eg, those with polycystic ovary syndrome or poor ovarian reserve). The incorporation of algorithms when planning the stimulation could improve safety and patient satisfaction without compromising IVF outcome.

Abstract

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