The Fertility Feed

A randomised controlled trial (R.C.T.) was set up to compare two groups of women who are poor ovarian responders (P.O.R.), to assess how effective either recombinant human-F.S.H. on its own or in combination with recombinant human-LH is at promoting egg development. Safety aspects of both treatments were also analysed. Other clinical trials suggest that adding Luteinising hormone to the treatment regime could improve reproductive outcomes. However, these trials did not use a stringent method for describing the poor ovarian response (P.O.R.) in the patients, and as the results were generated from a mixed group it is difficult to analyse the data. For this study, women were selected based on P.O.R. as described by the E.S.H.R.E. Bologna criteria to control risk in the study. In this trial, all of the women were treated with the same downregulation protocol, the long GnRH agonist method. Following downregulation, nine hundred and thirty nine (939) women were randomly assigned to one of the two treatment groups for ovarian stimulation. The results of this study include the primary outcome, that is, the number of eggs retrieved, and safety considerations and adverse events, including O.H.S.S. (ovarian hyperstimulation syndrome). Lastly, since the researchers had categorised P.O.R. for individuals, they were able to investigate any correlation between treatment group and patient characteristics. Looking at the results, there was no statistical significant difference in the numbers of eggs retrieved in either patient group. When we look at the outcomes over the term of a pregnancy there is a slight increase in favour of F.S.H. only treatment, but the difference is not significant by the time of live birth. From a safety point of view, there is no noticeable difference between the treatments, and no pattern of treatment-related issues. What is interesting is the retrospective analyses, when patient characteristics and treatments were investigated. The researchers found that the F.S.H. / LH combination versus F.S.H. only, generate different results depending on the P.O.R. status of the woman. That is, F.S.H. and LH shows an increase in live births for the patients with moderate to severe P.O.R., and conversely, patients with mild P.O.R. have an increased chance of live birth within a F.S.H.-only protocol. In addition, the total pregnancy outcome failure decreased in F.S.H./LH treatment compared to F.S.H.-only, at 6.7 and 12.4%, respectively. These results do need to be considered with some caution. The R.C.T. was not set up to investigate differences in P.O.R. levels in response to the two treatments, and further studies are needed to confirm this data. Lastly, the patient-base for these studies was largely white, and the data may differ for different ethnicities.

Personalized medicine, that is, using our knowledge of an individual’s characteristics and circumstances to determine a targeted treatment, is an emerging area for many medical conditions. It is early days for personalization in reproductive medicine. In fact, we still don’t know which areas of A.R.T. will lend themselves to an individual approach. However, if we look at the main sub-categories of the stepwise A.R.T. process flow, namely, ovarian stimulation, laboratory assessment, endometrial receptivity, embryo transfer, early pregnancy, and obstetric management, there are many, many treatment decision points and steps that could be targets for personalization, to meet the specific needs of the patient. For example, ovarian stimulation and laboratory assessment consist of a host of interventions and potential areas for personalization, including, for oocyte production, choice of stimulation protocol and gonadotrophin concentrations used, and, for lab testing, sperm quality assessment, fertilization method, and timing of egg transfer, are all potentially subject to individualization. Looking at meta-analyses of ovarian stimulation studies there is evidence to show benefits of personalized approaches in some areas, including drug concentrations used; in one study, ‘poor-responders’, identified by age-based, ovarian reserve calculations, show improvements in oocyte production when treated with an tailored dose of Follicle stimulating hormone (F.S.H.). In addition, the effect of ovarian hyperstimulation is a concern and can lead to cancellation of treatment, and this is also an area that shows promise when looking at drug concentration in specific groups. We say ‘shows promise’ since the studies producing the information are not always of sufficient quality, power or validity. In the same way, with the other areas of the A.R.T. flow, there is a mix of strong-, weak- and no evidence to support personalization, depending on the specific area being investigated. To prove benefits of personalization in A.R.T., the most scientifically sound method is a randomised controlled trial, which compares the ‘standard’ treatment with a personalized method. However, given the number of patients that are required for a robust assessment, we need to look at alternative study designs that minimise bias, account for the heterogeneity introduced in A.R.T. by patients and healthcare professionals, and optimise relevant outcome data. To meet these requirements, it is likely that multi-centre studies will be needed. Some innovation in study design and outcome analysis will be vital to ‘feed in to’ an emerging personalized A.R.T. treatment protocol that encompasses not only clinical areas highlighted here, but also patient expectations and psychological impact.

The meta-analysis was done under the P.R.I.S.M.A. and the Cochrane collaboration methodology, to test the benefits of Follicle stimulating hormone (F.S.H.) only as a treatment against F.S.H. with Luteinising hormone (LH), F.S.H. with human Chorionic Gonadotrophin (hCG), and human Menopausal Gonadotrophin (hMG). Studies were selected for analysis based on strict inclusion and exclusion criteria. Since the A.R.T. method used for any patient was not a reason to include or exclude a study from the analysis, results were further broken down into different sub-groups, depending on down regulation protocols.From an initial pool of 196 relevant articles, in seventy (70) of them, assessing the primary outcome of oocyte numbers retrieved, the authors found that treatment with F.S.H. alone resulted in more eggs than F.S.H.+LH, and conversely, hMG treatment led to higher numbers of oocytes retrieved. On other hand, for metaphase II oocytes (M.I.I.), there was no difference between F.S.H. and any of the other treatments. One benefit to consider when combining two drugs is the possibility of using a lower concentration of F.S.H., as is the case of F.S.H. with LH. However, this analysis does show that combining F.S.H. with hCG does not lead to a lower concentration of F.S.H. needed for each oocyte retrieved.Other important results include hMG treatment which led to an increase in embryo numbers and implantations, compared to the F.S.H. alone. Also, F.S.H.+LH compared to F.S.H.-only resulted in a significantly increased pregnancy rate by 1.2 times – an unexpected outcome as F.S.H. + LH produces fewer oocytes. However, the increased number of oocytes from hMG treatment does not increase the pregnancy rate.Further analysis based on downregulation methods was done and found that the increased pregnancy rate for F.S.H.+LH regime was only significant where GnRH agonist downregulation protocols are used.Only a few articles (12) reported live birth rates, but lacked specific details on protocol differences. It is important to remember that a relationships between oocytes retrieved and live birth rates is not generally agreed, given the many confounding factors that occur throughout an A.R.T. protocol pathway. These factors include, sperm quality for embryo development, endometrium thickness for implantation, and many others.In general, the findings of this meta-analysis support previous (in vitro) research that showed different gonadotrophins have different clinical actions when used during controlled ovarian stimulation.Looking at the choices for controlled ovarian stimulation and the solid evidence that shows significant differences depending on the drug of drug combinations used, it is clear that this is an area where A.R.T. could be tailored to the specific needs of individual women – effectively personalising the treatment protocol.