Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

18. Management of High Responders

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

The prevention of ovarian hyperstimulation syndrome (OHSS) should be of paramount importance as it is by far the most serious complication of both ovulation induction and IVF. OHSS is an iatrogenic condition caused by overdosing with gonadotrophin stimulation and is therefore almost totally preventable. High responders to gonadotrophin stimulation are the group who are susceptible (age <30 years, polycystic ovaries, lean body habitus, previous cycle with a high response) as they will produce a large number of follicles which predispose to OHSS. Both AMH and AFC have a high predictive value for the high responder and correlate well with each other. The secret of management for the high responder is to anticipate which women are likely to fall into this category and adjust the starting dose and stimulation protocol accordingly. In ovulation induction, only a chronic low-dose protocol should be used and for IVF, a GnRH antagonist protocol is preferred as this demands less gonadotrophins, is more patient friendly and allows the use of a GnRH agonist trigger of ovulation. This latter action, in place of an hCG trigger, will prevent OHSS but needs strong luteal support or a ‘freeze-all’ policy to maintain pregnancy rates.

Keywords

Ovarian hyperstimulation syndromeOHSSOvulation inductionIVFGonadotrophinFolliclesPolycystic ovariesAnti-Mullerian hormoneAMHAntral follicleGnRHAntagonistOestradiolLHOvulationStimulationAgonisthCGLuteotrophic effectOvulationFSHOocyte donorsOocyteEndometriumCorpora luteaLuteal phaseProgesteroneVitrificationEmbryosFrozen-thawed cyclesFresh transfer cyclesEgg-freezingPCOSMetforminHyperinsulinaemiaInsulin resistanceCarbergolineIn-vitro maturation

The prevention of ovarian hyperstimulation syndrome (OHSS) should be of paramount importance for the fertility practitioner as it is by far the most serious complication of both ovulation induction and IVF. OHSS is an iatrogenic condition caused by overdosing with gonadotrophin stimulation and is therefore almost totally preventable. High responders to gonadotrophin stimulation are the group who are susceptible as they will produce a large number of follicles which predispose to OHSS. The secret of management for the high responder is to anticipate which women are likely to fall into this category and adjust the starting dose and stimulation protocol accordingly. This applies to both ovulation induction and ovarian stimulation for IVF. The approach to the high responder undergoing ovulation induction has been described in Chap. 9 on chronic low-dose gonadotrophin therapy. Here we will concentrate on the management of the potential high responder who is about to undergo IVF and those who have a high response during stimulation.

18.1 Prediction of the High Responder

Clinically, those who can be anticipated to have a high response are those who have:

·               Age <30 years

·               Polycystic ovaries

·               Lean body habitus

·               Previous cycle with a high response

In addition to these clinical pointers, an examination of anti-Mullerian hormone (AMH) and an antral follicle count (AFC) can be highly predictive of a high response. The following are the cut-off values that our department finds useful to predict a high response but these may vary in different units according to the assay or equipment used.

·               AMH >30 pmol/l

·               AFC >12

Both AMH and AFC have a high predictive value for the high responder and correlate well with each other. Once the prediction of a high responder has been made, the stimulation protocol can be individually tailored. This mainly involves a choice of a GnRH agonist or antagonist and the starting dose of FSH for stimulation.

18.2 Preference of an Antagonist Protocol

Controlled ovarian stimulation for IVF involves the development of a number of follicles which produce rising levels of oestradiol. Without pituitary suppression, these would induce a surge of endogenous LH release. Traditionally, a long GnRH agonist protocol has been used to prevent this but today the tide has changed and the antagonist is now widely used, particularly for the high responder. There are several reasons for this change of attitude. According to the latest Cochrane analysis, the antagonist is now yielding a similar live birth rate to the agonist. This, after a long learning curve, has persuaded many units to switch to the antagonist which has some advantages over the agonist in that cycles are shorter, less gonadotrophins are required and there are no hypo-oestrogenic side effects, all of which are more patient friendly. Most importantly for the high responder, the use of an antagonist protocol enables the use of a single-shot GnRH agonist trigger of ovulation in place of the conventional hCG. This, of course, cannot be used when an agonist has been given as the GnRH receptors have been down regulated. The importance of this will be described below but clearly the antagonist protocol should be used for the predicted high responder.

18.3 Starting Dose for Stimulation

The starting dose of gonadotrophin stimulation for the predicted high responder must necessarily be lower than the dose used in conventional protocols for the predicted normal or low responders. We would recommend a daily starting dose of not more than 150 IU.

18.4 Agonist Trigger

In a conventional IVF cycle hCG is used to trigger ovulation usually when three or more follicles reach a diameter of 17 mm. hCG acts as a surrogate for the LH surge which triggers ovulation in a normal cycle. The hCG trigger has a half life of about 34 h and has a prolonged luteotrophic effect. However, although this prolonged effect is good for implantation, in susceptible patients such as high responders, it may induce OHSS. If hCG is withheld from these overstimulated cases, OHSS does not occur.

The substitution of hCG by a GnRH agonist produces an LH (and FSH) surge with amplitudes similar to those seen in a normal ovulatory cycle, sufficient to trigger ovulation but with a much less prolonged action than hCG. This led to the idea that using an agonist rather than an hCG trigger could prevent OHSS [1] (Fig. 18.1). It was also thought the FSH release induced would be an additional bonus as it may improve embryo quality.

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Figure 18.1

The agonist trigger for ovulation

However initial clinical trials, summarised in an updated Cochrane analysis in 2011 [2], proved disappointing. Although no OHSS was recorded in the agonist trigger group, live birth rates were very significantly decreased when compared with antagonist cycles with an hCG trigger. In an attempt to find the reason for this, oocyte donors were given either an agonist or hCG trigger in an antagonist cycle. As these produced similar outcomes in the recipients, it became clear that the miserable pregnancy rate seen in the clinical trials was not due to a detrimental effect on oocyte quality or endometrium but an insufficient stimulation of the corpora lutea and a consequent insufficiency of the luteal phase. A successful attempt to overcome this was made by employing massive luteal support (daily oestradiol patches with 50 mg of progesterone in oil) [3]. This maintained a good pregnancy rate while eliminating OHSS. Humaidan’s group then took up the challenge of boosting luteal support and examined the administration of 1,500 IU of hCG on the day of oocyte retrieval following the agonist trigger [4] (Fig. 18.2). This regime produced equivalent pregnancy rates to those using an hCG trigger.

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Figure 18.2

Agonist trigger with luteal phase support with 1,500 IU hCG on the day of ovum pick-up (OPU) (Humaidan et al. [4]). No significant difference in outcome compared with hCG trigger

Despite the success of strengthening luteal support in agonist triggered cycles, an agonist trigger followed by a ‘freeze-all’ policy is undoubtedly the most successful. A multicentre study recruited women at risk of developing OHSS during an antagonist cycle [5]. They were given an agonist trigger followed by vitrification of all 2-pro-nucleate embryos. Thawed embryos transferred in a subsequent cycle produced an excellent live birth rate. Assuming that frozen-thawed cycles are now producing similar pregnancy rates to fresh transfer cycles, this method does seem to be the future in eliminating OHSS in susceptible cases while maintaining good pregnancy rates. The fact that embryos are transferred to a non-stimulated endometrium rather than one stimulated by possibly detrimentally high levels of oestradiol also adds to its attraction.

Although severe OHSS occurs in “only” 2 % of cycles, its consequences demand the utmost attention for its avoidance. The use of an antagonist protocol with an agonist trigger, especially using a ‘freeze-all’ policy, is capable of completely eliminating OHSS and maintaining good pregnancy rates. As well as for high-responding women, its use has become virtually mandatory for cases in which OHSS must be avoided and the luteal phase is inconsequential; oocyte donors and cycles for egg-freezing.

18.5 Oral Contraceptive Pre-treatment

Pre-treatment with combined oral contraceptives is mainly used for help in the timing of the treatment cycle, mainly for the avoidance of egg collection during weekend breaks, as a withdrawal bleeding can be easily programmed. However, it has been reported that this method adversely affects pregnancy rates in antagonist cycles [6]. Although this was found in all-comers, we have found it useful for predicted high responders, particularly those with PCOS, in dampening the response. This is however merely observational and trials are warranted.

18.6 Metformin

Women with PCOS have a high incidence of insulin resistance and hyperinsulinaemia. This makes them even more susceptible for an exaggerated response to FSH stimulation. Metformin, an insulin lowering medication, has been employed as pre-treatment before and during stimulation for this group of women undergoing IVF. Initial trials demonstrated a decrease in the incidence of OHSS and even improved pregnancy and live-birth rates. Further trials are needed to confirm these findings.

18.7 Carbergoline

Recently, the dopamine agonist carbergoline has been used as a secondary prevention intervention for women at high risk of OHSS undergoing IVF. A meta-analysis of seven studies showed that carbergoline reduces the occurrence of moderate-severe OHSS without any apparent negative impact on the outcome of treatment [7].

18.8 In-Vitro Maturation (IVM)

IVM naturally avoids the need for stimulation or at least involves minimal medication for women with PCOS undergoing IVF. Oocytes recovered from unstimulated or minimally stimulated cycles are matured in culture, fertilised and the embryos replaced or frozen. This of course eliminates any chance of OHSS and reduces the cost of medication. Results however have, in the main, been disappointing and only specialised centres are using IVM as a routine procedure for these cases. With the inception of the agonist trigger to avoid OHSS and the good results obtained in general for women with PCOS undergoing IVF, I remain unconvinced that IVM with its hard work for the embryologist and disappointing results, is the treatment of choice for the high responder.

References

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Engmann L, DiLuigi A, Schmidt D, et al. The use of gonadotropin-releasing hormone agonist to induce oocyte maturation after co-treatment with GnRH antagonist in high-risk patients undergoing in-vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril. 2008;89:84–91.PubMedCrossRef

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Humaidan P, Bredkjaer HE, Westergaard LG, Andersen CY. 1,500 IU human chorionic gonadotropin administerd at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril. 2010;93:847–54.PubMedCrossRef

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Leitao VM, Moroni RM, Seko LM, Nastri CO, Martins WP. Carbergoline for the prevention of ovarian hyperstimulation syndrome: systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2014;101:664–75.PubMedCrossRef