Myths And Facts

Poor ovarian reserve has been a problematic unresolved issue with the Reproductive Specialists. Unfortunately, there is no universally accepted definition for the `low', `poor', `bad' or `non'-responder, although these patients have much lower pregnancy rates compared with `normal' responders. Numerous criteria have been used to characterize poor response. The number of developed follicles and/or number of oocytes retrieved after a standard-dose ovarian stimulation protocol are two criteria for defining poor ovarian response. This number has varied from 3-5 in various studies.(Land et al, 1996;Raga et al, 1999, Surrey et al., 1998). A peak estradiol varying from 300 -500 pg/ml during stimulation has been suggested by some. ( Raga et al, 1999). An elevated day 3 FSH level ranging from >7 to >15 mIU/ml has been proposed as an additional criterion to define poor ovarian response ( Karande et al, 1997; Faber et al, 1998).There have been other biochemical and radiological markers of poor ovarian response, basal antral follicle count being one of most popular one. So far poor follicular growth after ovarian stimulation has been considered a common indicator of poor ovarian response.

Many permutation and combination of treatment has been advised , some proven and some not. In this era of evidence based medicine we need to evaluate our practices on scientific data and proof.

This chapter evaluates certain current practices in the field of Reproductive Medicine which are aimed at improving ovarian response.

Myth : Increasing the dose of gonadotrophin to very high doses (600 IU daily) will improve ovarian response.
Fact: There is a ceiling response to gonadotrophins. The only systematic review found in this search for evidence was that of Tarlatzis et al. (2003). The authors concluded that studies using high doses of gonadotrophins for ovarian stimulation in poor responders have inconsistent conclusions and that the few prospective randomised studies have shown either minimal or no benefit at all. Most studies have concluded no improvement in pregnancy rates when the dose is increased to more than 450 iu daily in women with poor ovarian response. In two recent reviews (Borini and Dal Prato 2005; Dorn 2005), it was made clear by the authors that increasing the dose of recombinant FSH does not compensate for the decline in retrievable oocytes, and that higher doses are required only in overweight patients, marginally improving live birth rates. In a review from the Centre for Clinical Effectiveness (2000), searching for evidence for the effectiveness of increasing the total dose of FSH above 3,000 IU for ovulation stimulation of poor responders in assisted reproduction programmes, the authors, identifying five studies (included in the present search), concluded that there was no consistent definition of a poor responder and that there was no advantage of the longer, higher dose protocol.

Myth : Increasing the dose depending on follicular response beyond the early follicular phase will improve ovarian response.
Fact: Follicular recruitment occurs only in the early follicular phase of the menstrual cycle. Van Hoof et al. (1993) reported that a 450 IU daily dose of HMG given to 46 'low responders' from cycle day 8, had no effect on the number of mature follicles, number of oocytes retrieved and pregnancy rates, compared with the 22 controls, being given a 225 IU regime. The authors concluded that such an approach was ineffective in enhancing ovarian response in low responders, this being in accordance with the hypothesis that follicular recruitment occurs only during the early follicular phases of the menstrual cycle.

Myth : No particular gonadotrophin is better than other in improving pregnancy outcomes in poor responders.
Fact: The use of rFSH versus purified FSH in poor responders was evaluated in a small (15 versus 15 patients), prospective randomized study (Raga et al., 1999). The authors found an increased mean number of oocytes collected (7.2 versus 5.6), improved pregnancy rates (33 versus 6%) and lower cancellation rates (13 versus 40%). Similarly, another prospective study, albeit with historical controls (De Placido et al, 2000), assessed the efficacy of 300 IU rFSH versus the same dose of purified FSH in the flare-up protocol involving 28 cycles of poor-responder patients in each group. These authors suggested that rFSH was associated with a significantly larger number of oocytes retrieved (2.4 versus 1.7) and significantly increased pregnancy rates (14.3 versus 0%). It seems therefore, that there is evidence that rFSH produces better results in poor responders, though larger prospective randomized trials are needed to elucidate this issue further.

Myth : Certain gonadotrophin regimens have been definitely proven to be superior to others in poor responders.
Fact: Most randomized controlled studies have not documented any significant improvement in pregnancy rates when different protocols were compared. However , certain non randomized prospective studies have shown better outcome with specific regimes.

Stop Lupron regimen
This involves stopping the GnRH agonist with the onset of menstruation. This may help in multifollicular recruitment without unnecessary suppression. Two randomized controlled trials compared the effect of the “stop” versus “nonstop” long GnRH protocol on pregnancy rates in poor responders undergoing IVF (Dirnfeld et al. 1999) and (Garcia-Velasco et al 2000). However, pooling the results of the above studies did not suggest that an improvement in pregnancy rates is likely to be present with the stop agonist protocol.

Flare up regimen
In this protocol, GnRH agonist is started on day 2 and gonadotrophins on day 3. The principle is to use the flare response of the agonist and combine it with the gonadotrophin to recruit more follicles. This can be further modified by lowering the dose of the agonist (microdose)and stopping the agonist within 3-4 days (ultrashort). In another prospective study, 80 poor responders were treated using a classic flare-up GnRH agonist regimen with 450 - 600 IU/day of HMG from cycle day 3 and resulted in a satisfactory number of retrieved oocytes (10 ± 6.6 per cycle), but a low pregnancy rate per transfer of 13.4% (Karande et al. 1997). In contrast, high pregnancy rates per transfer (29 and 41.7%), but low number of oocytes at retrieval, were reported when the same protocol was applied in two other studies of poor responding patients (Padilla et al. 1996; Surrey et al. 1998).However, based on the results of a single underpowered study (Weissman et al 2003), the probability of clinical pregnancy does not seem to be dependent on the type of GnRH agonist protocol used.

GnRH antagonist protocol
The rationale for using GnRH antagonists in patients with poor ovarian response is based on the fact that endogenous gonadotropin secretion is not suppressed during follicular recruitment (Tarlatzis et al 2003) and(Craft et al 1999) .The use of a GnRH antagonist, clomiphene citrate and a mean of FSH of 375 IU/day (reaching in some cases doses over 600 IU) in 24 cycles of poor responders was reported to increase the number of retrieved oocytes per cycle (6.4 vs 4.7) and the pregnancy rates per transfer (23.5 vs 10%) when compared with their previous cycles, but not significantly (Craft et al. 1999). Based on the results of a single underpowered study (Marci et al 2005), the probability of ongoing pregnancy does not appear to be associated with the type of GnRH analogue used for LH surge inhibition. However, because significantly better results were demonstrated with the use of GnRH antagonists regarding duration of stimulation and total dose of gonadotropins required, as well as number of oocyte complexes retrieved, further comparative studies might be necessary.Three eligible randomized trials were identified, which evaluated a GnRH antagonist versus a GnRH agonist protocol in poor responders. A meta-analysis of these studies suggests that clinical pregnancy rates is not dependent on the type of analogue used, using the above stimulation protocols.

Fact : Addition of recombinant LH in ovarian stimulation protocols in poor responders may improve pregnancy rates.
Although no significant differences in clinical and ongoing pregnancy rates were found, a study conducted by Mochtar et al in 2007 indicated a beneficial effect of co-treatment of rLH. It was foun that poor responders especially benefited.

Myth : A Natural cycle IVF definitely improves pregnancy outcomes.
Fact: Some authors have proposed that if a woman does not respond to ovarian stimulation, then the use of her own natural cycle oocyte(s) should be considered. This approach is less invasive and less costly for the patient. Although the results of many studies have been published in the area of natural cycle IVF, very few have involved solely poor responders. In a study, which was prospective in nature and included historical controls (Bassil et al., 1999), it was suggested that the outcome was improved, with a mean of 0.9 oocytes per cycle(versus 1.5) being aspirated. In addition, the cancellation rates were significantly lower (18.8 versus 48%) and ongoing pregnancy rates per cycle were higher (18.8 versus 0%).By contrast, in another prospective study with historical controls (Feldman et al., 2001), comparable results were reported between the natural and stimulated cycles, in which at least one oocyte was aspirated in 82% of the patients while the full-term pregnancy rate was 9%. Similar results were found in a prospective study with no controls (44 cycles), in which patients aged over 44 years (i.e. potential but not proven poor responders) were included (Bar Hava et al., 2000). Successful oocyte aspiration was achieved in almost half of the cycles (48.5%),and the ongoing pregnancy rate was 2.08% per cycle. Morgia et al’s study in 2004 did not suggest that such a strategy is beneficial, regarding clinical pregnancy rates.

Fact : Oral contraceptive pre-treatment helps in improving outcome.
Oral contraceptive pill administration aims to suppress endogenous gonadotrophins and, at the same time (through its estrogen component), generate and sensitize more estrogen receptors. Unfortunately, the administration of COC (combined oral contraceptive pill) acts as a type of pituitary suppression in its own right. A few prospective and randomized studies have shown that COC pretreatment may be beneficial with regard to ovarian response and clinical pregnancy rates (Gonen et al., 1990; Biljani et al., 1998). This suggestion was not confirmed by pre-treatment with progestins alone (Shaller et al., 1995), although the data were obtained from a patient cohort which excluded poor responders. Although several investigators have used COC pretreatment in other experimental protocols for poor responders, only one retrospective study has been reported on this topic (Lindheim et al., 1996). These authors showed that COC administration prior to the GnRH- agonist protocol was associated with higher pregnancy rates and lower cancellation rates. In conclusion, although there is a general feeling that COC pretreatment might be of assistance in the ovarian response of poor responders, only a minimal amount of published data exists to further corroborate this.

Fact : Addition of Dexamethasone may improve ovarian response in poor responders.
To date, no studies have been reported involving poor responders. In one double-blind, placebo-controlled prospective randomized study in 290 cycles of normal responders (aged <41 years),dexamethasone was administered at 1 mg/day in the long luteal protocol until the day prior to oocyte retrieval (Keay et al.,2001), and the authors found a significantly lower cancellation rate (2.8 versus 12.4%, P = 0.001These findings provided great encouragement, as they reveal a very low incidence of poor response with the use of corticosteroids; however, the data are limited and can only be considered as preliminary.

Fact : Addition of other adjuvants may improve ovarian response in poor responders.
Growth Hormone
Both animal and human data have shown that growth hormone plays an important role in ovarian steroidogenesis and follicular development (Jia et al 1986)and (Doldi et al 1996). Treatment with GH enhances the gonadotropin effects on granulosa cells(Lanzone et al 1992).The results of the quantitative data synthesis, based on limited evidence, suggest that live birth rates are improved when GH is coadministered during ovarian stimulation for IVF in poor responders. GH addition needs to be further evaluated in ovarian stimulation of poor responders undergoing IVF, especially in view of the rate difference observed in live birth following its addition (+16%).

Pyridostigmine
This is an acetylcholinesterase inhibitor which, by enhancing the action of acetylcholine, can inhibit somatostatin release in the brain and thus increase GH secretion . Based on the results of a small, underpowered study (Kim et al 1999), pyridostigmine addition does not appear to improve ongoing pregnancy rates in poor responders undergoing IVF.

Oral L-Arginine
Nitric oxide (NO), a product of L-arginine is an intra- and intercellular modulator in many biologic processes, including ovarian physiology . However, available data from a single, underpowered trial (Battaglia et al1999) do not seem to confirm the above hypothesis.

Transdermal Testosterone
It has been suggested that androgens play a critical role on follicular growth. Androgens receptors have been identified by immunochemistry in the human ovary. The addition of androgen during the early follicular phase might have a beneficial effect on the number of small antral follicles and improve the ovarian sensitivity to FSH. However, regarding the probability of pregnancy, a single, underpowered study(Massin et al 2006) did not suggest that live birth/delivery rates are improved with the addition of transdermal testosterone.

Letrozole
The selective inhibition of aromatase prevents the overall production of estrogens, and consequently, their negative feedback effects on the hypothalamus–hypophysis axis. In this way, the pituitary produces more FSH. In addition, the inhibition of aromatase may increase the production of follicular androgens, which might improve follicular sensitivity or stimulate IGF-1. However, based on the results from a single, underpowered study(Goswami et al 2004) no improvement in pregnancy rates appears to be present with letrozole addition to FSH.

Myth : ICSI is better than conventional insemination in poor responders.
Because poor responders are usually characterized by retrieval of a limited number of oocytes, it has been hypothesized that ICSI might improve fertilization rates compared with conventional IVF, and thus lead to enhancement of the probability of pregnancy in these patients. On the basis of a single, underpowered study ((Moreno et al 1998), it appears that pregnancy rates are not dependent on the method of fertilization.

Fact: Day 2 transfer is better than day 3 transfer in poor responders.
Because of concerns regarding the impact of in vitro culture conditions to the limited number of developing embryos in poor responders, it has been proposed that shortening the duration of embryo culture might be associated with an improvement in pregnancy rates by increasing the number of embryos available for transfer. This hypothesis was confirmed in a single study by Bahceci et al in 2006.

Myth : Assisted hatching of zona pellucida improves pregnancy rates in poor responders.
The concept of this intervention is to increase the implantation potential in the few embryos that poor responders produce. The routine use of assisted hatching of the zona pellucida remains controversial, though it has been suggested that women with multiple IVF failures or those aged over 38 years might benefit from standard application of this technique (Cohen et al., 1992; Stein etal.,1995).Nevertheless, the published studies evaluate the use of assisted hatching in patients with poor prognosis for IVF, and not in true poor responders. (Schoolcraft etal 1994, Mansoor et al 2000). Thus , appropriately powered studies need to be done to evaluate the role of assisted hatching in women producing fewer oocytes.

Conclusion
Despite the plethora of predictive tests for low ovarian response,the poor responder is revealed only during ovarian stimulation. Furthermore, there is no uniformity in the definition of the `poor' response, thereby rendering many of the clinical trials incomparable. Well-designed, large-scale, randomized, controlled trials are needed to assess the efficacy of the different management strategies. The current results which are available are perhaps somewhat disappointing, but this should not be too surprising as most poor ovarian response women appear to have occult ovarian failure. Thus, the exhausted ovarian apparatus is unable to react to any stimulation, no matter how powerful this might be. The ideal stimulation for poor responders still remains a challenge,The use of very high doses of gonadotrophins to stimulate the ovaries is clearly unavoidable due to the lack of any initial ovarian responsiveness. Nevertheless, the results have been controversial with the prospective randomized trials showing either minimal or no benefit. Additionally, the few available relevant studies have suggested that the use of recombinant FSH might improve outcome.

Although not derived from authentically prospective trials, optimistic data have been presented which suggest the bene®cial use oflare-up GnRH agonist protocols (standard or microdose) along with high doses of gonadotrophins These regimens seem to have better results compared with those of the standard long luteal protocols. A significant improvement was demonstrated with the use of the low-dose, midluteal onset, GnRH agonist regimens, that discontinue with the initiation of ovarian stimulation, followed by high doses of gonadotrophins (GnRH agonist `stop' protocols), according to the prospective studies with historical controls. However, the well-designed prospective trials failed to confirm this, and showed no significant improvement. The few data available from the use of the GnRH antagonists do not show any benefits at present, though it is possibly too early to comment at this time. Certainly, further evaluation in this area is necessary. Pretreatment with oral contraceptive may help the ovarian response and, therefore, appears to be beneficial. Likewise, adjuvant therapy with GH or GH-releasing factors causes in general either no change or a trend towards non-significant improvement. There appears to be some role of recombinant LH in ovarian stimulation protocols in poor responders.

Standard ICSI and assisted hatching techniques clearly need to be further assessed in proven poor responders, although the latter approach seems to benefit older IVF patients to a greater extent. Finally, natural cycle IVF although a longstanding option may be an appropriate and also affordable strategy for those poor responders who are capable of producing one or two follicles,with documented results being comparable to those achieved with stimulated cycles. Thus,systematic review and meta-analysis suggests that insufficient evidence exists to recommend most of the treatments proposed to improve pregnancy rates in poor responders. Currently, there is some evidence to suggest that addition of GH, as well as performing embryo transfer on day 2 versus day 3, appear to improve the probability of pregnancy.

Myths And Facts

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