Clinicians working in reproductive medicine aim to deliver optimal treatment that is cost-effective, provides satisfactory probabilities of success, and minimises risks and treatment burden for the patient. In this SHAPE in-clinic meeting, we will consider and discuss what optimal treatment entails and it can be provided.
Ovarian stimulation in older treatment protocols was complex, of long duration and often associated with a significant OHSS risk. Recently there has been a shift in treatment aims, towards treatment that lowers treatment burden, risk of complications, psychological problems, side effects, complexity, cost, and disparity in access.
Optimal treatment entails reducing treatment burden, by decreasing the number of injections and providing better tolerated therapy. Reducing the number of injections may be done by using a long-acting recombinant FSH: the first such compound is corifollitropin alfa, one injection of which can replace seven daily gonadotropin injections during the first week of stimulation. The number of injections may also be reduced through the use of GnRH antagonist protocols: in contrast to the long GnRH agonist protocol, which usually involves approximately 3 weeks of GnRH analogue treatment per cycle, a GnRH antagonist cycle usually requires only a few days of analogue administration.
Another aspect of optimal treatment is risk reduction. The stimulation of numerous dominant follicles increases the risk of ovarian hyperstimulation syndrome (OHSS). Several treatment elements can be modified or introduced to lower the risk of OHSS. In a Cochrane review, GnRH antagonist protocols were associated with a 39% relative risk reduction for severe OHSS, compared with agonist protocols. In a separate meta-analysis, the relative odds of hospital admission for OHSS was reduced by 54% with antagonists compared with agonists. In GnRH antagonist cycles, there is an option to use a GnRH agonist for triggering of final oocyte maturation, which can reduce or eliminate the risk of OHSS.<sup> </sup>Recent studies suggest that, with adequate rescue of the luteal phase, this approach may be a valid option in at-risk patients, but more evidence is required. Until the optimal type of luteal phase support is identified, freezing all oocytes or embryos after GnRH-agonist triggering for later frozen-thawed embryo transfer has been shown to be a reliable, safe and efficacious treatment option.
Optimisation progresses with accumulation of knowledge, through both clinical trial evidence and experience in normal clinical practice. It has taken more than 15 years to define the long GnRH agonist protocol, and not surprisingly, a number of different GnRH antagonist protocols have been proposed, showing that the modification process is still ongoing. There is a need to explore further the issues of hormonal assessment at the beginning of the GnRH antagonist cycle, cycle planning, optimal starting FSH doses for different patient groups, fixed vs flexible antagonist administration, and timing and doses of agents used to trigger final oocyte maturation. Nevertheless, on the basis of current evidence, many clinics use GnRH antagonist protocols successfully in the majority of patients with an a priori good response.
In most cases the introduction of such protocols has demanded a change in working practices, but this has been manageable through good inter-staff communication and effective scheduling. Changes in the number of procedures, Saturday working, and changes to staffing have been necessary, and computer scheduling can help the organisation of clinic workflow. There is some flexibility in the GnRH antagonist protocol, and certain steps (e.g. starting day of gonadotrophin and day of hCG administration) are frequently brought forward or backward, but more data are needed on this issue. Programming with oral contraceptives (OCs) is possible, but meta-analysis data show that this results in a lower ongoing pregnancy compared with protocols without OC programming.