This article has been reproduced with the author’s permission.
The concept of personalised medicine is not new, dating to the time of Hippocrates. The notion however has gained increased application in recent years with scientific breakthroughs in the understanding of disease processes and approaches to precision treatments. Personalised medicine has also extended into infertility management. One widespread practice is the application of prediction models for the treatment of anovulatory infertility and polycystic ovary syndrome.1 Current fertility practice, more so with in vitro fertilisation (IVF) treatment can be described as a form of stratified medicine, whereby treatments are matched to specific patient population characteristics using clinical biomarkers. There is a constant endeavour by clinicians, embryologists and scientists to providing tailored or individualised IVF treatments with the goal of maximising success rates and safety. For ease of application, modalities towards personalised IVF can be considered along the events of the treatment pathway starting with (1) pre-treatment prediction models, (2) individualised controlled ovarian stimulation (iCOS) regimens, (3) advanced technologies for selecting embryos with the best implantation potential and (4) the ideal luteal phase support.
Several prediction models have already been developed for IVF treatments.2 These models use clinical characteristics, medical history such as age, body mass index (BMI), duration of subfertility, type, cause of subfertility and biomarkers of ovarian reserve. The human ovary contains a fixed number of non-growing follicles (the ovarian reserve) established before birth that declines with increasing age until the menopause when the follicle pool is completely depleted.3 However, ovarian reserve at birth can vary substantially between women based on individual biology, which consequently influences the rate of depletion and ovarian reserve of individual women. Dynamic biomarkers, such as anti-mullerian hormone (AMH) and antral follicle count (AFC) can be used to accurately evaluate ovarian reserve, made possible by the fact that AMH is produced by granulosa cells in pre-antral and antral follicles which reflects the primordial follicle pool.4 Anti-mullerian hormone and AFC are the most sensitive ovarian reserve tests (ORTs) for the prediction of response following ovarian stimulation.5,6
Controlled ovarian stimulation regimens have undergone significant developments involving evolution of gonadotrophins from human-derived compounds to highly purified and recombinant products, development of several pituitary suppression regimens using either GnRH agonists or GnRH antagonists, use of different approaches to oocyte maturation and triggering, such as hCG or GnRH agonist administration. While these advances have improved the efficiency of ART, the rapid progress in our understanding of clinical biomarkers of ovarian reserve means that there is a renewed focus on personalised care in reproductive health, particularly with respect to individualising gonadotrophin dosage.7 There has also been a significant reduction in the risk of ovarian hyperstimulation syndrome (OHSS) with iCOS by avoiding very high gonadotrophin doses, use of GnRH antagonist regimen and GnRH agonist trigger for oocyte maturation. Validated models have been developed incorporating clinical characteristics and ovarian reserve biomarkers to individualise gonadotrophin doses demonstrating clinical benefit.8 A further extension has been innovative models incorporating AMH as a companion diagnostic along with body weight to derive the ideal personalised gonadotrophin dosing.9 The aim of such tested models is a move towards precision treatments to ultimately increase the efficacy and safety of ART.
Although personalisation in ART has been heavily focussed with COS regimens, it has extended beyond COS to laboratory procedures such as use of morphokinetics, preimplantation genetic screening (PGS) for embryo selection and personalised embryo transfer with use of endometrial receptivity array (ERA) based on gene expression. Furthermore, improvements in cryopreservation techniques such as vitrification has made possible the notion of cycle segmentation in IVF. Reproductive Medicine, particularly ART is a dynamic field with fast moving innovations. However, all such should be evaluated with robust clinical trials before routine clinical application.
Sesh K Sunkara MBBS, MD, MRCOG is a Consultant Gynaecologist and Sub-specialist in Reproductive Medicine at Barking Havering Redbridge University Hospitals Essex, UK
- Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab. 1998 Jul;83(7):2361-5.
- Leushuis E, van der Steeg JW, Steures P, Bossuyt PM, Eijkemans MJ, van der Veen F, Mol BW, Hompes PG. Prediction models in reproductive medicine: a critical appraisal. Hum Reprod Update. 2009 Sep-Oct;15(5):537-52.
- Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010 Jan 27;5(1):e8772.
- Karkanaki A, Vosnakis C, Panidis D. The clinical significance of anti-Müllerian hormone evaluation in gynecological endocrinology. Hormones (Athens). 2011 Apr-Jun;10(2):95-103.
- Broer SL, van Disseldorp J, Broeze KA, Dolleman M, Opmeer BC, Bossuyt P, Eijkemans MJ, Mol BW, Broekmans FJ; IMPORT study group. Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach. Hum Reprod Update. 2013 Jan-Feb;19(1):26-36.
- Broer SL, Dólleman M, van Disseldorp J, Broeze KA, Opmeer BC, Bossuyt PM, Eijkemans MJ, Mol BW, Broekmans FJ; IPD-EXPORT Study Group. Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis. Fertil Steril. 2013 Aug;100(2):420-9.
- La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014 Jan-Feb;20(1):124-40.
- Allegra A, Marino A, Volpes A, Coffaro F, Scaglione P, Gullo S, La Marca A. A randomized controlled trial investigating the use of a predictive nomogram for the selection of the FSH starting dose in IVF/ICSI cycles. Reprod Biomed Online. 2017 Apr;34(4):429-438.
- Nyboe Andersen A, Nelson SM, Fauser BC, García-Velasco JA, Klein BM, Arce JC; ESTHER-1 study group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril. 2017 Feb;107(2):387-396.
RG/519/2016/UK(3)e Date of preparation: March 2018