Homerton Fertility Centre, Homerton University Hospital, London, UK
For many years the principle adopted was that the greater the number of eggs retrieved, the greater the chance of a pregnancy. To achieve this aim, large doses of gonadotrophins are used, most commonly with a long GnRH agonist protocol. This regimen is long, expensive, requiring high gonadotrophin dosage and frequent monitoring and pre-disposes to ovarian hyperstimulation syndrome or, at the least, abdominal discomfort. Unsurprisingly, it was the foresight of Robert Edwards that first called for the use of milder stimulation protocols and a more patient-friendly and safer approach in 1996. Since then much attention has been paid to this proposed change in thinking and many different protocols have been devised with the purpose of easing the patient burden with increased safety and efficiency. It is difficult to recommend a natural cycle as results are so poor especially in older patients. A so-called modified natural cycle employing mild stimulation and a GnRH antagonist has also produced disappointing results. The integration of clomifene and of letrozole into protocols has decreased gonadotrophin consumption but little else. The principles involved in the search for an efficient mild stimulation protocol are both honourable and logical. The balance between patient comfort and cost and live birth rates has to be taken into account. This very much depends on the characteristics of the subject. While few have faith in natural cycles, other protocols described here show some promise in good prognosis patients and more well-conducted trials should establish their worth.
Mild stimulationIVFFertilisation Ovarian stimulation gonadotrophinsGnRHOvarian hyperstimulation syndromeOHSSPregnancyStimulation protocolsNatural cyclesLHOocytePremature ovulationGnRHMini IVFLate follicular phaseFollicle diameterDominant follicleMale infertilityFSHFollicular phaseEmbryoMultifollicular developmentEndometrialClomifeneAromatase inhibitorsLetrozoleEstradiolOvaryAndrogensPre-antral folliclesAntral follicles
Steptoe and Edwards achieved the first successful IVF live birth in 1978 using an unstimulated cycle. Shortly following this milestone, it became obvious that increasing the number of eggs retrieved and available for fertilisation would increase the pregnancy rate. Ovarian stimulation with gonadotrophins rapidly replaced natural cycles and pregnancy rates grew considerably. For many years the principle adopted was that the greater the number of eggs retrieved, the greater the chance of a pregnancy. To achieve this aim, large doses of gonadotrophins are used, most commonly with a long GnRH agonist protocol. This regimen is long, often involving weeks of daily injections, is expensive, requiring high gonadotrophin dosage and frequent monitoring and pre-disposes to ovarian hyperstimulation syndrome or, at the least, abdominal discomfort. With the addition of the emotional stress involved in this relatively complex process, it is a testing ordeal for the couples to undergo which, in more cases than not, will not result in a pregnancy.
Unsurprisingly, it was the foresight of Robert Edwards that first called for the use of milder stimulation protocols and a more patient-friendly and safer approach in 1996. Since then much attention has been paid to this proposed change in thinking and many different protocols have been devised. The improvement in laboratory efficiency has made these advances feasible but each protocol has its distinct plusses and minuses.
19.1 Natural Cycles
The use of natural cycles for IVF is turning full circle back to the days of Edwards and Steptoe in the late 1970s. They comprise of monitoring the cycle until the onset of the LH surge and the retrieval of one oocyte. Natural cycles can certainly be described as ‘patient-friendly’ as they are less demanding physically, cheap (less than 25 % the cost of a conventional cycle), and safe. But have we forgotten that the object of the exercise is to achieve a pregnancy? The problems that affect the success of natural cycles are many and include premature LH rises and premature ovulation (causing cancellation in 20 % of cycles) and a too large percentage of cycles in which no egg is retrieved. Problems in planning and coordination with the laboratory only add to these. A top ongoing pregnancy rate of around 7 % per cycle is commonly quoted .
I have written of my perplexity and inability to understand the use of natural cycles for poor responders (Chap. 17) but what of other patient groups? With whatever protocol to which they have been compared, the results of natural cycles have been much the worse . This led to the idea of offering natural cycles as a series of treatments. In studies of well selected patients, 4–11 natural cycles are variously calculated to produce the same live birth rate as one conventional cycle. Considering the time invested in oocyte retrievals and not least, the stress of the couples awaiting the results of the pregnancy test and their frequent disappointments, it is difficult to condone natural cycles as the protocol of choice.
19.2 Modified Natural Cycles
The relatively disappointing results when employing a natural cycle led to the development of a ‘modified natural cycle’. This ‘mini IVF’ stimulation protocol involves the administration of a GnRH antagonist during the late follicular phase, usually with a dominant follicle diameter of about 14 mm, and then daily 75–300 IU of gonadotrophins to boost the growth of the dominant follicle (Fig. 19.1). This regimen, compared with the natural cycle approach reduced the number of cancelled cycles from 20 to 30 %. However, in a large group of young, good prognosis women undergoing their first IVF cycle, the ongoing pregnancy rate was 8.3 % per cycle using this protocol . Although this is a safe and relatively patient-friendly protocol, results are again disappointing. It may find a place for young couples with severe male infertility.
The suggested use of a GnRH antagonist in a modified natural cycle. (a) In a single dose; (b) in a multiple dose protocol
19.3 Delayed Low-Dose FSH with GnRH Antagonist
Taking one step up from a modified natural cycle, in an attempt to improve pregnancy rates while achieving an improved degree of patient comfort compared with conventional protocols, FSH stimulation is started later in the follicular phase (day 5–7), usually in a dose of 150 IU. An antagonist is given to prevent premature LH surges and a single embryo transfer is performed. The reasoning behind this protocol is that exogenous FSH will prevent a decrease in endogenous levels and that this is enough to induce multifollicular development. Compared with conventional long agonist protocols less oocytes are harvested but their quality and implantation potential may be superior. The reasons for this are that high levels of oestrogens seem to have a negative effect on endometrial, oocyte and embryo quality. In addition, the trend towards single embryo transfer in good prognosis patients places less demand on the number of oocytes needed. A randomised, non-inferiority trial studied a late-start, low-dose FSH stimulation in an antagonist protocol with a single embryo transfer compared with a standard long agonist regimen with transfer of two embryos . There was no difference between the two protocols in terms of cumulative live birth rates or patients’ discomfort but the mild protocol had less multiple pregnancy and was overall, less expensive.
19.4 Clomifene Combined with Gonadotrophins
The main purpose in the use of clomifene citrate, usually given in a dose of 100 mg/day from the early follicular phase and combined with gonadotrophin administration, is to decrease the amount of gonadotrophins required. This utilises the property of clomifene to cause a release of endogenous FSH early in the cycle. The trials of this regimen are very heterogeneous and it is difficult to formulate a conclusion regarding its’ worth. A Cochrane analysis  suggested that the combination of clomifene with gonadotrophins (with or without a GnRH antagonist) did not differ significantly from gonadotrophins in agonist protocols in terms of pregnancy rates but had reduced rates of OHSS. More trials were called for.
19.5 Aromatase Inhibitors Combined with Gonadotrophins
The aromatase inhibitor letrozole has two properties that could suggest its’ use in mild stimulation protocols. Similarly to clomifene, it induces an endogenous FSH release but also, the blocking of estradiol production from androgens induces an increased concentration of androgens in the ovary. As androgens promote the early development of follicles, they increase the number of pre-antral and small antral follicles available for stimulation (See Chap. 8). Small trials in poor responders have shown mixed results when letrozole administration in a dose of 2.5–5 mg/day was combined with gonadotrophins but have shown some promise in normal responders. The use of letrozole for this purpose has been severely limited due to the restrictions placed on its use for this indication by the drug company due to unsubstantiated data regarding possible teratogenicity. It is hoped that further large controlled trials of the use of letrozole in IVF will be forthcoming.
The principles involved in the search for an efficient mild stimulation protocol are both honourable and logical. The balance between patient comfort and cost and live birth rates has to be taken into account. This very much depends on the characteristics of the subject. While I have little faith in natural cycles, other protocols described here show some promise in good prognosis patients and more well-conducted trials should establish their worth.
Pelinck MJ, Hoek A, Simons AH, Heineman MJ. Efficacy of natural cycle IVF: a review of the literature. Hum Reprod Update. 2002;8:129–39.PubMedCrossRef
Verberg MFG, Macklon NS, Nargund G, et al. Mild ovarian stimulation for IVF. Hum Reprod Update. 2009;15:13–29.PubMedCrossRef
Pelinck MJ, Vogel NE, Hoek A, et al. Cumulative pregnancy rates after three cycles of minimal stimulation IVF and results according to subfertility diagnosis: a multicentre cohort study. Hum Reprod. 2006;21:2375–83.PubMedCrossRef
Heijnen EM, Eijkemans MJ, De Klerk C, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet. 2007;369:743–9.PubMedCrossRef
Gibreel A, Maheshwari A, Bhattacharya S. Clomiphene citrate in combination with gonadotrophins for controlled ovarian stimulation in women undergoing in vitro fertilization. Cochrane Database Syst Rev. 2012;(11):CD008528.