Pretreatment with oral contraceptive pills to identify poor responders that may benefit from rLH supplementation during GnRH-antagonist treatment for IVF: A pilot perspective study proposal

Controlled ovarian stimulation, using a gonadotrophin-releasing hormone (GnRH) antagonist protocol, is a potential treatment option for women with a low response to other fertility treatments as it appears to be at least as effective as GnRH agonists (long protocol). However, previous studies have indicated that the administration of GnRH antagonist may cause an excessive reduction in endogenous luteinizing hormone (LH) levels. The use of recombinant LH (rLH) supplementation during ovarian stimulation is controversial. The present article proposes a future study focused on women aged ≥40 years old, with the aim of identifying patients who are poor responders to GnRH-antagonist treatment that may benefit from rLH supplementation. We hypothesize that patients with suppressed hypothalamic-pituitary-axis activity may benefit from rLH supplementation, as GnRH-antagonist administration has the potential to induce a marked reduction in LH levels in such patients compared with that in patients that exhibit a regular recovery following the administration of oral contraceptive pills (OCPs). Furthermore, patients with hyper-responsive hypothalamic-pituitary-axis activity may be affected by ‘low-gonadotropin-responsiveness’, similar to that observed in patients with any mutation in the follicle-stimulating hormone (FSH) receptor, who are known to benefit from rLH supplementation. The proposed pilot study would include 120 women who are predicted to be poor responders to GnRH-antagonist treatment. All subjects will be allocated at random (using 2:1 computerized randomization) into two study groups: Group A (OCP-treated) and group B (control). For all patients, the serum values of FSH, LH and 17β estradiol (E2) will be detected on day 3 of the menstrual cycle preceding OCP treatment (baseline) and at day 4 following OCP treatment. The Δ-variation from baseline levels for all markers, the FSH/LH ratio and the E2/FSH ratio will be determined. Δ-variation from the baseline of the FSH and LH values will be used to further categorize group A patients into subgroups A1–4, based on respective quartile numbers (Q1–4). Patients admitted to each of the four subgroups A1–4, based on their FSH quartile, will be selected at random to receive rLH supplementation (ratio, 1:1) during ovarian stimulation. If the resulting data are able to identify women that may benefit from rLH supplementation during ovarian stimulation, a large part of inconclusive evidence regarding rLH supplementation will be clarified. If patients supplemented with rLH (according to abnormal recovery of hypothalamic-pituitary-axis activity after OCP treatment) exhibit an improved ovarian response during in vitro fertilization (IVF) and subsequent pregnancy rate, the pre-IVF OCP test could be adopted as a useful tool for improving the success rate of assisted reproductive technologies in poorly-responding patients.