Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

17. Management of Poor Responders

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

Few problems in IVF are more frustrating than the poor responder to gonadotrophin stimulation, most commonly seen in advanced fertile age but also after ovarian surgery, advanced endometriosis, endometriomas, obesity, previous pelvic infection/adhesions, smoking, post chemotherapy/radiotherapy. Many definitions have been proposed but the most widely accepted definition of a poor response is <3 oocytes retrieved using maximal ovarian stimulation. An AMH <3 pmol/l or antral follicle count of <5 is predictive of low response which, depending on female age, would generally also predict a low chance of pregnancy. An age of >37 years is by far the most important predictor of a low response and consequently a low live birth rate. From this age on there is a steep downward slope in the number of follicles in the cohort available that are able to respond to stimulation. There is a plethora of treatment modalities that have been proposed for the poor responder, bearing witness that none of them have been successful and that you cannot stimulate follicles that aren’t there. Only testosterone patches and letrozole have offered some glimmer of hope for treating the poor responder but evidence is inconsistent and flimsy.

Keywords

IVFGonadotrophinPre-ovulatory folliclesOocytesOestradiolFSHInhibin-BAntral follicleAnti-Mullerian hormoneAMHGnRHOvarian stimulationOvarian reserveFolliclesEndometriosisEndometriomasBody mass indexPelvic adhesionsPelvic infectionSmokingChemotherapyRadiotherapyAnti-Mullerian hormoneAMHAntral folliclesOestradiolInhibin-BLuteal phasehMGNatural cycleICSIOHSSAdjuvant therapiesInsulin like growth factorHypogonadotrophic-hypogonadismAntral folliclesOvarian sensitivityLetrozoleDehydroepiandrosteroneAndrogenPremature ovarian failureFolliculogenesisStimulation protocolrFSHAspirin

Few problems in IVF are more frustrating than the poor responder to gonadotrophin stimulation, especially when this is unexpected and the patient young. A poor response is most commonly seen in advanced age, obesity or following ovarian surgery. It is a well known fact that there is a direct relationship between the number of embryos available for transfer and pregnancy rates and it follows that poor responders have low pregnancy rates. However, this generalization is tempered by the ongoing debate of the definition of a poor responder, the fact that some poor responders who are young will conceive with relative ease and that the quantity of oocytes obtained does not always reflect quality. Optimal stimulation of the poor responder remains a challenge and requires particular attention to achieve a good reproductive outcome.

17.1 Definition

The most widely accepted definitions of a poor response have been based on the number of pre-ovulatory follicles developing or number of oocytes retrieved, <3 developing pre-ovulatory follicles and <3 oocytes retrieved being the most popular [1]. These are often linked with maximum oestradiol concentrations achieved, <500 pg/ml often being taken as a marker. Although predictors of ovarian response such as day 3 FSH levels, inhibin-B, day 3 oestradiol, antral follicle count, anti-Mullerian hormone and dynamic tests with clomiphene and GnRH agonists are all in use, it would seem eminently sensible to make the diagnosis while actually administering gonadotrophins in a treatment cycle, whatever criteria are used. Common sense also dictates that the definition of poor responders should include the degree of ovarian stimulation used and this over two cycles as a low response in one cycle may be coincidental. A low oocyte number has only been found to be detrimental to pregnancy rates if the cumulative dose was >3,000 IU FSH in patients aged <40 years [2]. Cancellation of a cycle due to poor response to 300 IU/day or more of FSH was associated with a significantly worse prognosis in these patients. The official ESHRE Consensus definition states that the presence of two of the three following features is deemed necessary to define poor response:

1.

2.

3.

The definition was modified to add “expected” in those cases where no previous response had been recorded or had not been through ovarian stimulation. In the risk factors retrieval of four or less oocytes was accepted as a cut off point for POR. My feeling is that this definition is far too broad and will include too large a number of the present day IVF population to be useful clinically or for research.

17.2 Aetiology

An age of >37 years is by far the most important predictor of a low response and consequently a low live birth rate. From this age on there is a steep downward slope in the number of follicles in the cohort available that are able to respond to stimulation (Table 17.1). As a wise man coined it: “You cannot stimulate follicles that aren’t there!” In the younger age group, aetiological factors include previous ovarian surgery, advanced endometriosis, endometriomas, high body mass index, previous pelvic infection/adhesions, smoking, post chemotherapy/radiotherapy and, rarely, FSH receptor polymorphisms.

Table 17.1

The aging ovary

Birth

1–2 million germ cells

Menarche

300,000 follicles

35–37 years

10,000–25,000 follicles

50 years

1,500 follicles

Menopause +3 years

0

17.3 Predictive Markers

Forearmed is forewarned. If a poor response is predicted before the first stimulation cycle, then appropriate planning of the protocol can be made. This can limit the number of cycles cancelled and shorten the cycle so avoiding undue discomfort. In addition to the woman’s age there are several markers that can aid this prediction (See Chap. 5). Anti-Mullerian hormone (AMH) serum concentrations are among the best of these. They have a low inter-cycle variation and so can be measured at any point during the cycle and correlate strongly with the number of antral follicles available for stimulation. Antral follicle count (AFC) is similarly predictive although, unlike AMH, is observer dependent. An AMH level of <3 pmol/l and a total AFC of <5 can usually be relied upon to predict a poor responder. An estimation of FSH serum concentrations on day 2–4 of the cycle has been the traditional way to estimate ovarian reserve. This route is falling out of favour as often large intra-cycle variations are seen, it must be measured on specific cycle days and it less reliable in those aged <40 years old. If day3 FSH is used, an oestradiol estimation should be made at the same time and if found to be >200 pmol/l combined with a high FSH, the predictive value for a poor response is enhanced. Other tests, much more rarely used are inhibin-B serum concentrations, ovarian volume and assessment of ovarian vascularity. Dynamic tests involving the FSH response to clomifene or to one injection of GnRH analog or simply to see the response to exogenous FSH, have been largely abandoned with the introduction of AMH and AFC to the armamentarium.

17.4 Proposed Therapeutic Options

There are a plethora of treatment modalities that have been proposed for the poor responder (Table 17.2). The length of this list illustrates the profound lack of success of any of them to corner the market. There is a notable lack of large randomised trials and the heterogeneity of the definition of the poor responder has made interpretation even more difficult. In the recent Cochrane review, out of the ten trials, only one reported live birth rate [1]. Some of these proposed methods will be described briefly here.

Table 17.2

Treatment options proposed for poor responders

High dose gonadotrophins

GnRH antagonists

Low dose GnRH agonist

Oral contraceptives

Flare-up

DHEA

Stop protocol

Testosterone

Ultra-short protocol

Letrozole

Short protocol

Growth hormone

Pyridostigmine

LH

Oral L-arginine

Natural cycle

Aspirin

17.4.1 High Dose Gonadotrophins

The first instinct on spotting a poor responder is to increase the dose of FSH or try starting a new cycle with a higher dose. Up to a daily dose of 300 IU FSH this may be of help as it is possible that the increase in dose was needed to reach the individual threshold. However, it is highly unlikely that daily doses above 300 IU/day will improve the prognosis.

17.4.2 GnRH Agonist

Manipulation in the use of the GnRH agonist has been tried in several directions: Short (flare-up) protocol, mini-dose, stopping the agonist before gonadotrophin stimulation (cessation protocol), micro-dose flare-up. Of these, only the short flare-up protocol (short and ultra-short) have been widely accepted. Advantages with this approach are that the ovarian suppression is not excessive and the initial stimulation of the GnRH receptors and consequent secretion of endogenous gonadotrophins enhances the effects of the exogenously administered gonadotrophins. However, there is little convincing evidence of its efficacy. Late luteal phase initiation of a short course of low-dose agonist discontinued before gonadotrophin stimulation has also been proposed.

17.4.3 GnRH Antagonist

With the more widespread use of the antagonists today, the clinician may now address the poor responder patient from a new perspective. The addition of the GnRH antagonist to stimulation protocols prevents premature LH surges while not causing prolonged suppression in the early follicular phase, a crucial time for poor responder patients. Only few prospective randomized trials have compared GnRH antagonists to various agonist protocols in groups of variously defined poor responders. These include trials of the antagonist compared with microdose agonist flare, full dose agonist flare and a standard long agonist protocol. None of these demonstrated a significance advantage in pregnancy rates of the antagonist. However, an antagonist protocol is now often selected for the poor responder as it usually involves the requirement of significantly less gonadotrophins and a shorter duration of stimulation compared with the long agonist.

The use of protocols involving clomiphene, with or without gonadotrophins, has been disappointing for poor responders and the use of recombinant, rather than urinary FSH or hMG has done little to improve results.

17.4.4 Natural Cycles

Such is the predicament of the poor responder to conventional stimulation for IVF that a movement to promote the use of natural cycles (usually combined with ICSI) has taken root lately. This is a direction whose logic fails me. The main reason given for this strategy is that if there is little response to stimulation then a cycle not involving medication for a woman who is an ovulating naturally would produce the same results, save expense and increase patient comfort and avoid OHSS and multiple pregnancies. However, the success rate with natural cycles is very low per treatment cycle started and is a much less effective treatment option not only due to high cancellation rates because of a premature LH surge and also high risk of failure to retrieve an oocyte but also the fact that these patients have only one embryo available for transfer if they are lucky. The number of cycles women need to go through in order to achieve successful oocyte retrieval, fertilisation and embryo transfer is high when compared to a conventional stimulation cycle. This can give unrealistic hopes for women who keep trying cycle after cycle for a long time if not counselled adequately. This can have a huge psychological impact. With the best available evidence this seems to be an unrealistic option, but can be considered only as a last resort before egg donation after counselling the patients. Egg donation no doubt offers the most effective treatment for this subset of patients. The fact that gonadotrophin stimulation is saved is no reason to suggest that the probability of success with a maximum of one egg is better than in those who have responded poorly to stimulation.

17.4.5 Adjuvant Therapies

The number of adjuvant therapies that have been suggested to improve the lot of the poor responder is enough to fill a separate book (Table 17.2).

There is a complex intra-ovarian regulating system involving insulin like growth factor (IGF-1) with ligands, receptors and binding proteins. The presence of receptors for GH and IGF-1 in the ovary and the ability of IGF-1 to improve the response of granulosa cells to FSH suggested a role for GH in human reproduction. Based on the theory that growth hormone could act as a co-gonadotrophin, we first tried to show that treatment with GH could have the potential to improve the ovarian response to gonadotrophin stimulation in women with ovaries that are relatively resistant to human menopausal gonadotrophin (hMG) therapy. However further randomised, well controlled studies using GH failed to demonstrate any significant beneficial effects on the outcome of IVF cycles in poor responders. The use of GH was really only found to be successful for GH-deficient patients in increasing ovarian sensitivity to gonadotrophin stimulation and in particular, those who had hypogonadotrophic-hypogonadism. A recent resurge of interest in the use of growth hormone for poor responders has been sparked by a very heterogeneous collection of studies containing small numbers of subjects. I remain unconvinced that the enormous expense involved in administering growth hormone co-treatment is justified for poor responders except for those who are deficient in IGF-1. Based on similar principles, the use of growth hormone releasing factor and pyrostigmine have been tried with no or very limited success.

The fact that androgens play a critical part in follicular growth and that androgen receptors are present in the human ovary suggests that the use of androgens during the early follicular phase might have a beneficial effect on the number of small antral follicles and improve the ovarian sensitivity to FSH. The impression from the first few trials employing trans-dermal testosterone patches is positive. If further large RCT’s confirm the findings of these initial studies, the logical use of androgens to promote follicular growth may well be the most promising treatment so far suggested for the poor responder. As letrozole, an aromatase inhibitor, blocks the production of oestrogens from androgen, there is a small build up of androgens within the follicle. On the same principle of androgen stimulation of early follicular growth, letrozole has been tried to improve the response to gonadotrophins by previous poor responders. So far, the results have been mixed and there is also the problem that letrozole is off-label for this indication in most countries. Dehydroepiandrosterone (DHEA) is a weak androgen which is sold over the counter in the USA and is being strongly promoted as a rejuvenator. Over the last decade, DHEA has been widely employed by numerous specialists for the treatment of premature ovarian failure, premature ovarian aging or diminished ovarian reserve sufferers wishing to achieve pregnancy. There is no firm evidence base for this treatment as all the studies so far have been observational and mainly from one group. A number of independent randomised controlled trials now being performed will demonstrate the worth, or otherwise, of this mode of treatment. Its widespread adoption despite the lack of solid evidence once again demonstrates the desperate plight of the poor responder.

It has been proposed that small doses of LH, when used early in ovarian stimulation in IVF cycles, have a beneficial effect on the quality of oocytes, a very important factor especially in cases in which few embryos are available for transfer. In poor responders, it was thought that LH administration in the early phase of folliculogenesis, early during the stimulation protocol, may have a beneficial effect on the maturity and fertilisability of oocytes. However, several recent randomised trials have failed to show that increased pregnancy rates are achieved in patients for whom LH was added to rFSH for ovarian stimulation in poor responders or indeed in women over the age of 35 years.

The use of aspirin to improve ovarian blood flow and hopefully ovarian response has been equally disappointing.

17.5 Conclusions

The poor response to ovarian stimulation for IVF, especially in the older women, remains the bête noir of this procedure. This is reflected in the literature, whether from meta-analyses or consensus meetings, which repeatedly states that there is insufficient evidence to support the use of any particular intervention in the management of poor responders. A poor responder usually carries a poor prognosis for an ongoing pregnancy. The exception to this rule is the young poor responder with whom it is often worth persisting, even with limited embryos for transfer. This is further fuel to the notion that age is the best predictor of oocyte quality while ovarian response to gonadotrophins is the best predictor of ovarian reserve. A combination of advanced age and a poor ovarian response to gonadotrophins carries the worst prognosis for pregnancy.

References

1.

Pandian Z, McTavish AR, Aucott L, Hamilton MP, Bhattacharya S. Interventions for ‘poor responders’ to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev. 2010;(1):CD004379.

2.

Kailasam C, Keay SD, Wilson P, Ford WCL, Jenkins JM. Defining poor ovarian response during IVF cycles, in women aged <40 years, and its relationship with treatment outcome. Hum Reprod. 2004;19:1544–7.PubMedCrossRef