The management of patients with impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation has challenged reproductive specialists for a long time. Apart from our limited understanding of its pathophysiology, there is extensive heterogeneity in the definition of the poor responder patient as well as overall disappointing outcomes in assisted reproductive technology (ART) cycles.
The Bologna criteria for poor responders (ESHRE, 2011) was introduced in 2011 with the primary objective of selecting homogeneous groups of patients based on ‘oocyte quantity’ for testing in prospective randomized trials (RCT) for different strategies. Up to now, more than 70 RCT have compared interventions in poor responders using a vast range of patient inclusion criteria, including the Bologna criteria. Interestingly, among the trials registered in clinicaltrials.gov (up to November October 2016), 44 were specific to POR, but only seven trials enrolled an adequate sample size to avoid a type II error. Analyzing results of the completed trials and published literature, the overall conclusion is that there is insufficient evidence to support the routine use of any particular intervention either for pituitary down-regulation, ovarian stimulation or adjuvant therapy. It can be therefore concluded that little progress has been achieved in the clinical management of POR, thus frustrating clinicians and patients alike.
A critical shortcoming of the existing POR criteria is that women with POR may comprise subgroups with diverse baseline characteristics. Despite the strong relationship between the number of retrieved oocytes and female age in ART due to the inexorable depletion of follicle pool with aging, there exists a large biological variability in the number of non-growing and growing follicles within the same age group. Hereditable factors, genetic and medical conditions, as well as lifestyle and environmental chemicals impact not only the establishment of the primordial follicle pool during fetal life but also the reproductive function in adult women, thus contributing to the observed interindividual variability. Moreover, the ovarian sensitivity to exogenous gonadotropins is also variable and modulated by genetic factors involving both the gonadotropins and their receptors. These are the reasons why reduced ovarian reserves should be discriminated from poor/suboptimal ovarian responses to gonadotropins caused by inherent ovarian resistance (e.g., genetic polymorphisms). However, at present, it is not clear whether the Bologna criteria (or any other criteria) for POR can eliminate clinical heterogeneity within the poor responder population. It can be thus argued that analysis of whole populations of POR with different baseline characteristics and, therefore, different prognosis in a given RCT may dilute the effect size.
In clinical terms, counting the number of oocytes retrieved or estimating such numbers using ovarian biomarkers may not be enough for clinical management. Equally important is the age-related decrease in oocyte quality that mostly depends on chromosomal abnormalities occurring before meiosis II. Despite recognizing that other biochemical processes may also be relevant to oocyte quality, including mitochondrial dysfunction, oxidative stress, and increased cumulus and granulosa cell apoptosis, the genetic competence of oocytes is paramount as it will affect the implantation potential of resulting embryos into the uterus. Whereas embryo euploidy rates of about 60% are observed in younger women (
From the clinician standpoint, it seems that the published POR criteria have offered little help to understanding the complexity of the problem. In a recent international survey among clinicians, the most used criterion for identifying POR was the “number of follicles produced”, which surprisingly has rarely been included in the definition of POR by scholars (IVFonline.org). And due to the absence of efficient remedies, most practices do not use evidence-based treatment for this category of patients. Furthermore, according to RESOLVE, a not-for-profit patient organization dedicated to providing education to couples suffering from infertility, POR are those women who require large doses of medication and who make less than an optimal number of oocytes (resolve.org). Not surprisingly, patients themselves have introduced a new element into the already complex POR equation, namely, suboptimal response to ovarian stimulation. As it stands, it was sound to assume that anyone -scholars, clinicians, and patients- has been entirely satisfied with the existing criteria for the diagnosis of low responders because they fail to provide a clear path for management. These are the reason why the POSEIDON Group was created, i.e., to shed light into the definition and management of Low Prognosis Patients (LPP) undergoing Assisted Reproductive Technology (ART).