Reproductive Medicine - Is low intensity stimulation always "better" stimulation?

Summary of the talk by Nicolas Zech at COGI 2015


Controlled ovarian stimulation (COS) is an integral part of IVF and is closely related to the IVF outcome.

Thus, choosing the appropriate stimulation strategy is crucial to therapy success.

Various therapy concepts and even more stimulation protocols claim to be the optimal therapy and to improve outcome with minimal or no side effects. However, the goal of ovarian stimulation is not only the transfer of an embryo, but the birth of a healthy baby, preferably with a single stimulation.

Despite a wealth of publications on COS, there are still open issues regarding:

(i) best medical practice concerning the type of stimulation protocol,

(ii) costs per successful pregnancy related to certain stimulation protocols, and

(iii) how to manage the risks of COS, including ovarian hyperstimulation syndrome (OHSS) and poor or low response after stimulation.

Physicians are often afraid of providing the best available treatment options to their patients due to restrictive legal situations. In some countries (e.g., Italy and France), OHSS cases must be reported directly to the state and/or federal authority in the form of so-called “vigilance messages”. In the case of repeated occurrence of OHSS at a particular institution, the authority initiates further investigations. Thus, in many IVF centers, stimulation cycles are often cancelled if serum estradiol (E2) levels exceed a certain value. However, the crucial question is whether serum E2 concentration is a reliable predictor of OHSS. Additionally, this raises a question regarding optimal treatment of OHSS.

Are the current treatment regimens of inpatient management (hospitalization), still the best options to deal with moderate and severe OHSS? In this legal environment, several IVF centers have opted for a strategy to attract patients by offering so-called “light IVF”, “soft stimulation” “mild stimulation IVF”, “low-cost IVF”, “low-dose IVF” or “natural-IVF”, to name but a few. These regimens are either based on:

1) non-controlled ovarian stimulation (non-COS) (natural-IVF without administration of fertility drugs or based on e.g. anti-estrogens/aromatase inhibitors/low dose FSH, but without having control over the LH-surge through Gonadotropin-Releasing-Hormone agonist [GnRHa] or GnRH antagonists i.e. modified natural-IVF) or

2) non-conventional controlled ovarian stimulation (non-cCOS), which uses low dose hormonal follicle stimulation and GnRH agonists or antagonists.

With such alternative regimens, these centers promise OHSS-free therapy and reduced treatment costs. GnRH agonist (GnRHa) or antagonist protocols applying higher FSH doses have been the basis of conventional controlled ovarian stimulation (cCOS) for several years. However, in recent years, cCOS has been increasingly categorized as “aggressive stimulation”. What does this term really mean?

This talk aims to shed some light on this discussion. Moreover, the outcome and cost calculations of non-COS/non-cCOS vs. cCOS-based IVF therapies will be critically scrutinized. If a fertility clinic is applying non-COS or non-cCOS, we must bear in mind that on average 1-3 mature oocytes are harvested (depending on the type of non-cCOS). In contrast, in a normal responder patient following classic cCOS, on average 8-12 mature oocytes should be retrievable; otherwise, this would be considered under-treatment at the expense of the patient. Numerous publications have demonstrated a maximum of 10-20% pregnancy rates (PRs)/implantation rates (IRs) can be achieved with 1-3 oocytes. Clinics have repeatedly claimed non-cCOS with low dose stimulation to be superior.

However, there has been criticism regarding lack of properly designed studies, inaccurate data, and risky data interpretation. With the rise of blastocyst culture techniques and in vitro blastocyst selection, all fertilized oocytes are kept in culture until day 5. Thus, the fittest embryos to reach the blastocyst stage are selected. Moreover, with the move toward single embryo transfer protocols and new technical innovations in IVF, high cumulative PRs can be achieved using classic cCOS.

This talk will further explore whether a non-COS or non-cCOS strategy is truly more effective or less costly. In addition, we will give a short overview of the terminology and management of poor and low responder patients. Finally, we will outline our approaches beside a summary and discussion of the current knowledge regarding the best stimulation policy.

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