Rationale: It is shown in a number of publications that long term pituitary down-regulation for three to six months prior to IVF/ICSI improves clinical pregnancy rates in patients suffering from endometriosis. However, discussion about this treatment strategy exists, as both the Cochrane and ESHRE recommendation are based on only three small studies. These studies are executed in a different IVF/ICSI treatment era in which more aggressive stimulation was used followed by transferring two or more embryos instead of single embryo transfer which is the current standard. Being afraid that prolonged down-regulation with a GnRH agonists may lower the response to ovarian stimulation (especially in patient with a poor response in previous IVF/ICSI treatments), it is conceivable that clinicians nowadays may be sceptical about this treatment regime. In addition, uncomfortable side effects, such as vasomotor instability, are often related to this treatment regime, which make patients frequently unwilling to use GnRH agonists for a longer period of time. Alternatively, the effect of continued use of oral contraceptives (OCs) for six to eight weeks prior to IVF/ICSI has also been investigated. These observational data show that this treatment might be beneficial in patients with severe endometriosis undergoing IVF/ICSI, as clinical pregnancy rates were improved compared to endometriosis patient treated without OCs and similar to that of control patients without endometriosis. Those results in combination with the direct costs of GnRH agonists (€ 370,- per 3 months) versus oral contraceptives (€ 41,- per 3 months) and indirect costs (higher loss of productivity during GnRH agonist treatment makes it interesting to investigate whether the outcome of continuous use of OCs is as effective as long term pituitary down-regulation with a GnRH agonist prior to IVF/ICSI, which has not been investigated yet.
Objective: To show a non-inferiority of continuous use of oral contraceptives for three months to long term pituitary down-regulation with a GnRH agonist for three months prior to present-day IVF/ICSI protocols in patients with severe endometriosis (ASRM stages III and IV).
Study design: Prospective randomised controlled, parallel two-arm study. Patients who do not wish to participatebe randomized will be asked to participate in a prospective cohort study.
Study population: Patients with endometriosis ASRM III or IV, with an indication for IVF/ICSI. Number of patients to be included in the RCT 330 (non-inferiority design, power 80%, α 0.05, margin 3%, 10% drop-out). In the cohort study 400 patients will be included.
Intervention: Continuous use of oral contraceptives for three months (intervention group) versus long term pituitary down-regulation with a GnRH agonist for three months (reference group) prior to IVF/ICSI.
Main study outcome: Primary outcome: live birth rate after fresh embryo transfer. Secondary outcomes: cumulative live birth rate after one IVF/ICSI treatment cycle including fresh and frozen embryo transfers up to 15 months after randomisation, ongoing pregnancy rate, time to pregnancy, treatment outcome parameters (like number of oocytes), adverse events, complications, recurrences (recurrence of endometriosis complaints, radiologic or surgical confirmed recurrence of endometriosis or the need to restart endometriosis therapy), quality of life, safety, cognitive failures due to hormonal treatment, patient preferences and costs effectiveness (direct and indirect costs).
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: As both treatment protocols are not experimental and already used in daily practice, no additional risks or burdens are expected from the study. All measurements will be combined as much as possible with routine investigations. All possible sides effects and severe adverse events will be monitored and evaluated. No untoward effects of continuous use of oral contraceptives prior to IVF/ICSI on treatment outcome (i.e. ongoing pregnancy) are expected. Non inferiority of continuous use of oral contraceptives can improve patients comfort by eliminating the side effects related to long term pituitary down-regulation with a GnRH agonist. An IVF/ICSI treatment strategy with continuous use of oral contraceptives holds promise to be more patient friendly as well as cost-effective compared with long term pituitary down-regulation with a GnRH agonist.