Homerton Fertility Centre, Homerton University Hospital, London, UK
The stresses and strains, trials and tribulations, expectations and disappointments that infertile couples must endure still need to be lessened. The adoption of ‘softer’ protocols for ovarian stimulation is becoming more widespread and the more patient-friendly GnRH antagonist protocol is taking over from the traditional long agonist protocol. Ovarian stimulating agents free from extraneous proteins are now self-injected from pen devices and slow-release preparations of FSH lessen the number of injections. The development of an oral preparation of FSH is proving more than a stern challenge but is, nevertheless, expected to materialize sometime in the future. Oral preparations of a GnRH analogue are maybe more of a pipe dream whereas an OHSS-free clinic is a distinct possibility. The widespread use of time lapse imaging is expected to considerably improve embryo selection for transfer and this will surely increase the use of elective single embryo transfer. A whimsical prediction for an IVF protocol in 2025 would include oral preparations of FSH and GnRH antagonist, an oral agonist trigger with a ‘freeze-all’ regimen and replacement of embryos, one at a time, in a subsequent natural cycle. More seriously, until infertility is recognized as a health problem by governing authorities, in these days of rising costs of medication and technology, not a small number of couples will find themselves childless and denied treatment simply because of a lack of funds. This prevention of a basic human right on these grounds, I find immoral and unacceptable. If we have the capability to treat, this should not be denied the patients.
Ovarian functionPsychologistSocial workerMild protocolsOvarian stimulationGnRH antagonistGnRH agonistsFSHFreeze-dried lyosphereGonadotrophinHuman recombinant FSH agonistCorifollitropinIVFhCGOvarain hyperstimulation syndromeOHSSKisspeptin agonistKisspeptin antagonistMild stimulationOvulationAgonist triggerElective single embryo transferFrozen-thawed natural cycleMultiple pregnanciesTime-lapse imagingICSIEmbryo morphologyMorphokineticsMorulaBlastocystEuploidyEgg donationSocial egg freezingVitrificationDonor eggsStem-cell technologyAnovulatoryObstructed Fallopian tubesSub-standard spermOvulation inductionOvarian stimulationMorbidityMultiple pregnancy ratesIUIEmbryo selection
22.1 Patient Comfort
Over the years the efficiency and efficacy of both ovulation induction and controlled ovarian stimulation have improved considerably. Protocols have been modified and ovarian function manipulated to achieve the best pregnancy rates. The stresses and strains, trials and tribulations, expectations and disappointments that infertile couples must endure still need to be lessened. Most units now employ a psychologist/social worker who is available to relieve some of the tensions involved. The adoption of ‘softer’ protocols for ovarian stimulation is becoming more widespread and slowly but surely, the more patient-friendly GnRH antagonist protocol is taking over from the traditional long agonist protocol. Less close monitoring and hospital visits are now the rule and the advent of ovarian stimulating agents that, due to their purity and freedom from extraneous proteins, can be self-injected sub-cutaneously, has gone some way to increasing patient comfort. The emphasis of the drug companies has now turned to improved delivery systems on the one hand and ways to lessen the number of injections on the other.
22.1.1 Drug Delivery Systems
Traditionally, FSH for injection has been provided as a freeze-dried lyosphere to be dissolved in water for injection before being drawn into the injection syringe. Most gonadotrophin preparations are now available as ready-to-use preparations, provided in a pen injection device which comes preloaded and can be used for multiple injections. The use of a pen device has a number of tangible advantages over the usual syringe injections. The FSH dose can be accurately titrated and so drug doses can be individualized for each patient. Injection pain is generally experienced less frequently using a pen device and in surveys conducted by the industry, most importantly, the patients have found a pen device to be more user-friendly then the conventional syringe.
Multiple injections remain one of the most tiresome parts of most infertility treatments. While it is too much to expect the development of an injection without a needle, we can expect less injections or, looking not too far into the future, the development of oral preparations of FSH, GnRH agonists and antagonists!
22.1.2 Less Injections
Now on the market is a chimeric long-acting human recombinant FSH agonist (corifollitropin). The mean half-life of the standard FSH preparations is around 32 h, necessitating daily injections, whereas the half-life of the long-acting preparations is extended to 4 days or more. The advantage is that a single injection of this new preparation could provide sufficient ovarian stimulation over a period of 7 days. Although this is not suitable for low-dose, subtle ovulation induction protocols, it will find a place at the beginning of controlled ovarian stimulation in preparation for IVF. Saving even five daily injections makes this drug more user-friendly. Topping-up with daily injections of the present recombinant preparations, if necessary following the approach of the termination of action of the long-acting preparation, until criteria for administering hCG are reached seems a feasible proposition. My personal feeling of a loss of control using long-acting preparations such as this is purely psychological, as long as the rate of OHSS can be maintained at zero levels.
As far as the GnRH agonists are concerned, the trend has been to prefer daily injections to a depot, slow release preparation, mainly due to the fact that the depot induces over-suppression and has an over-long duration of action. Regarding the GnRH antagonist, there is little to choose between comparisons of a single slow release dose or a multiple dose protocol requiring daily injections as far as outcome is concerned but it is the daily injection that has been preferred.
Rumour has it that the development of an oral preparation of FSH is proving more than a stern challenge but is, nevertheless, expected to materialize sometime in the future. Oral preparations of a GnRH analogue are maybe more of a pipe dream but in these days of rapidly advancing pharmaceutical techniques, just as recombinant technology has produced FSH, LH and hCG, then there may be some room for optimism. Looking further afield, is a kisspeptin agonist or antagonist a viable proposition?
22.2 Less Complications
Ovarain hyperstimulation syndrome (OHSS) and multiple pregnancies remain the scourge of the IVF practitioner. It does not take too much imagination to envisage an OHSS free clinic. Mild stimulation protocols employing a low dose of FSH in an antagonist protocol have already gone a long way to achieving this aim. The concept of using an agonist trigger of ovulation in place of hCG has made this wish a reality. If this protocol is combined with an elective single embryo transfer then not only will OHSS be eliminated but multiple pregnancy rates will be close to zero. While ideal for the young, good prognosis patients, an ideal individual protocol for the woman with poor ovarian reserve has yet to be found.
22.3 Better Results
22.3.1 Improved Protocols
Reported live birth outcomes are, at the best, on a par with natural conception and live birth rates per cycle. While this may be thought of as satisfactory, there is surely room for improvement. Milder stimulation protocols seem to counteract the deleterious effect of high oestrogen levels on the implantation capability of the endometrium. Although smaller numbers of oocytes are harvested with milder stimulation, the embryos formed are thought to be of better quality and heightened implantation potential. A further alternative would be to trigger ovulation with an agonist following stimulation in an antagonist cycle and freeze all embryos. These can then be transferred, one-by-one of course, in a frozen-thawed natural cycle. While eliminating the possibility of both OHSS and multiple pregnancies, the transfer of a well selected single embryo in a cycle devoid of endocrine disruptions surely promises an excellent pregnancy rate. My unwithered optimism would predict a cumulative conception rate of around 80 % for women under the age of 35 years.
22.3.2 Time-Lapse Imaging
Key to this ideal is the selection of the best embryo to transfer. Here we come to what may well turn out be the single most significant step forward in the field since ICSI. Time-lapse imaging of embryo development provides a wealth of information not only on the embryo morphology but also on the kinetics of cellular processes forming the morphology, known as morphokinetics. Up to now, the embryologist must remove the embryos from the incubator maybe once or twice on crucial days and select the embryo(s) to be transferred using morphological criteria which do not always correlate well with outcome. Time-lapse imaging provides a video of the embryo development and morphology and crucially demonstrates the rate of development. Predictive morphokinetic variables for identifying embryos with the best implantation potential have been defined for embryo cleavage points up to the 8-cell stage, and for morula and blastocyst formation, duration and synchrony of the cell cycles. While early studies have demonstrated variables for the prediction of embryos with implantation potential, for the superior prediction of day 3 embryos that will develop into blastocysts over and above that of senior embryologists and even for euploidy according to morphokinetics, the subject is still in its infancy. The incoming data will be further computerised and improvements made but I believe that this will prove to be a giant step in identifying the best embryo to transfer, especially important for the holy grail of elective single embryo transfer. Further reading is suggested at the end of this chapter for those interested in the details.
22.4 Less Optimistic Predictions
The increasing tendency to delay conception to an advanced female age is increasing the demand for egg donation. While public awareness of the availability of so-called ‘social egg freezing’ is growing and although vitrification techniques are a distinct improvement for egg survival, the demand for donor eggs is predicted to grow and legislation is predicted to stiffen so that demand may well shortly outstrip availability. Much effort is being invested in stem-cell technology to produce oocytes but I fear that in view of the obstacles so far encountered, this is still a long way from being a viable proposition.
Finally, we have not yet discovered how to lower female age! More precisely, how to deal with the aging female with a rapidly diminishing ovarian reserve. Despite the myriad proposals tried and tested, itself a testimony of the depth of the problem, I cannot see a solution being produced in the near future if at all.
There is no reason to suspect that rates of infertility will decrease in the future. A certain proportion of women will be anovulatory and some will have obstructed Fallopian tubes while some male partners (projected to be more than today) will have sub-standard sperm. Efforts to improve their lot can safely be predicted to continue.
Diagnostic tests need to be streamlined, made less invasive and to produce results more speedily. I can see no reason why a full diagnostic work-up should not be completed within 1 month. With the improvement and widespread publicity of advances in treatment, the public is less patient. They want to know where they stand and what the treatment possibilities are. As regards ovulation induction and ovarian stimulation, more consideration for the safety of the patient, e.g. the avoidance of ovarian hyperstimulation, is essential. Nobody should have to suffer severe morbidity as a result of fertility treatment which is, after all, almost always performed on patients who are in good general health. The reduction of multiple pregnancy rates, whether involving ovulation induction or ovarian stimulation for IUI or IVF, simply must be reduced. I believe that the advent of a widespread practice of using only low-dose gonadotrophin schemes for ovulation induction and single embryo transfer, made possible by improved methods of embryo selection, have already arrived but are not being utilized everywhere.
Despite the increasing demands and pressure from infertile couples (and some practitioners), there is no excuse for a ‘blunderbus’ approach, e.g. rushing patients through to IVF as a first line treatment despite the lack of an indication. The diagnosis and treatment of infertility and anovulation in particular, remain very logical, scientific subjects. Adhering to diagnostic schemes and logical treatment protocols while taking into account every couple’s individual needs and psychological approach to their problem, will bring the required results.
Inevitably, the question of finance arises. Until infertility is recognized as a health problem by governing authorities, in these days of rising costs of medication and technology, not a small number of couples will find themselves childless and denied treatment simply because of a lack of funds. This prevention of a basic human right on these grounds, I find immoral and unacceptable. If we have the capability to treat, this should not be denied the patients.
Finally, I have used my crystal ball to devise the ideal protocol that we will be using in maybe 10 years time. Whimsical or realistic? Time will tell (Fig. 22.1).
Imaginative IVF protocol in the year 2025. OPU ovum pick-up, eSET elective single embryo transfer
Suggested Further Reading on Time-Lapse Imaging
Conaghan J, Chen AA, Willman SP, et al. Improving embryo selection using a computer-automated time-lapse image analysis test plus day 3 morphology: results from a prospective multicenter trial. Fertil Steril. 2013;100:412–9.PubMedCrossRef
Herrero J, Meseguer M. Selection of high potential embryos using time-lapse imaging: the era of morphokinetics. Fertil Steril. 2013;99:1030–4.PubMedCrossRef
Herrero J, Tejera A, Albert C, Vidal C, de los Santos MJ, Meseguer M. A time to look back: analysis of morphokinetic characteristics of human embryo development. Fertil Steril. 2013;100:1602–9.PubMedCrossRef
Swain JE. Could time-lapse embryo imaging reduce the need for biopsy and PGS? J Assist Reprod Genet. 2013;30:1081–90.PubMedCrossRef