Conventional ovarian stimulation no longer exists: welcome to the age of individualized ovarian stimulation

Reproductive BioMedicine Online (2011) 23, 141– 148

www.sciencedirect.com www.rbmonline.com

COMMENTARY

Conventional ovarian stimulation no longer exists: welcome to the age of individualized ovarian stimulation Luciano G Nardo a,b,*, Richard Fleming c, Colin M Howles d, Ernesto Bosch e, Samir Hamamah f, Filippo M Ubaldi g, Jean-Noel Hugues h, Adam H Balen i, Scott M Nelson j a

Department of Reproductive Medicine, St Mary’s Hospital, CMFT University Hospitals, Manchester, UK; b GyneHealth, Manchester, UK; c GCRM Ltd, Glasgow, UK; d Merck Serono SA, Geneva, Switzerland; e Instituto Valenciano de Infertilidad, Valencia, Spain; f ART/PGD Department, Arnaud de Villeneuve Hospital, INSERM U847, University1 Montpellier, France; g Centre for Reproductive Medicine GENERA, Valle Giulia Clinic, Rome, Italy; h Reproductive Medicine Unit, Department of Obstetrics and Gynaecology Jean Verdier Hospital, University Paris XIII, France; i The Leeds Centre for Reproductive Medicine, Leeds, UK; j Division of Developmental Medicine, Reproductive and Maternal Medicine, University of Glasgow, UK * Corresponding author. E-mail address: [email protected] (LG Nardo).

Abstract The prediction of extremes of ovarian response to stimulation and the irreversibility of reduced ovarian reserve remain

important clinical and basic science research issues of IVF treatment. Recommending commencement of ovarian stimulation using any of the available exogenous compounds without knowledge of individual ovarian potentials is simplistic and dangerous because of the possible adverse consequences for the woman. The identification of groups of patients likely to benefit from one protocol than another is central to the workup process of IVF. Determining the agents for ovarian stimulation as well as the combination of them, the daily dose and duration according to some background information should be seen as the way to enhance safety and cost-effectiveness. This discussion paper aims to introduce the concept of individualized ovarian stimulation in routine clinical practice and to generate interest for tailored stimulation protocols. RBMOnline ª 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: anti-Mu ¨llerian hormone (AMH), chronological age, extremes of ovarian response, individualized ovarian stimulation, IVF

Introduction For more than two decades the long gonadotrophinreleasing hormone (GnRH) agonist protocol with maximal-dose gonadotrophins has been the mainstay of ovarian stimulation for IVF. Such an approach was largely welcomed for its efficient patient timetabling, low cancellation rates, high numbers of pre-ovulatory follicles, oocytes and embryos as well as for improved pregnancy rates (Hugues et al., 1992). Despite these significant advantages, over

time this long agonist/high-dose FSH protocol was claimed to be time-consuming, expensive and not patient friendly (Ubaldi et al., 2007). Instead, GnRH antagonist regimens, which facilitate shorter treatment times, lower total gonadotrophin doses and costs and reduced risks of ovarian hyperstimulation syndrome (OHSS), have been proposed as the principle approach to be adopted for IVF (Devroey et al., 2009). However, this ‘one size fits all’ is reminiscent of the same simplistic approach that was originally adopted for the long agonist protocols. In reality it is likely that

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there are patient cohorts which would be better served using the traditional long-course GnRH-agonist control; however, the key would be in identifying patients likely to benefit from one form of LH suppression rather than the other. The primary end-points would be the degree of ovarian response as a marker of safety and implantation and pregnancy outcomes. We wish to propose that an approach of individualized ovarian stimulation, utilizing a variety of options including both agonist and antagonist protocols based upon anticipated ovarian response, is more likely to attain optimal outcomes for patients and physicians. It will also allow a more standardized approach to ovarian stimulation. This paper, which follows an expert meeting held in Manchester, UK in November 2009, discusses and appraises the treatment options that have been considered by many as part of a tailored ovarian stimulation approach.

The downside of one size fits all: which approach is optimal? The initial trials comparing the performance of GnRH antagonists with agonists in selected patients proved unsatisfactory, and GnRH antagonists showed no superiority in pregnancy outcomes (Albano et al., 2000; Borm and Mannaerts, 2000). Meta-analyses have provided different conclusions with marginally lower pregnancy/ongoing rates and live-birth rates with the use of antagonists as compared with agonists (Al-Inany et al., 2006). However, these findings with respect to live birth have not been replicated by others (Kolibianakis et al., 2006). Inevitably, both these publications had methodological issues; the Cochrane analysis of Al-Inany and colleagues included non-peer-reviewed data and studies of intrauterine insemination, whereas Kolibianakis and colleagues excluded these studies but estimated some live births from ongoing pregnancies using a conversion formula of 84% of number viable at 7 weeks or 92% of number viable at 12 weeks of gestation. Furthermore, the confidence limits of Kolibianakis and colleagues are close to null and may be easily altered with further moderate-sized trials, as only the European trial (Borm and Mannaerts, 2000) exceeded 500 patients. Notably, restriction of meta-analyses to special patient groups including poor responders and those with polycystic ovary syndrome (PCOS) failed to demonstrate significant benefits with respect to clinical pregnancy (Griesinger et al., 2006). Therefore, based on the current analyses, a trend towards reduced success with antagonists would be a more accurate interpretation. On the other hand, there appears to be an Table 1

indisputable advantage in terms of the reduction of OHSS risk (Al-Inany et al., 2006; Griesinger et al., 2006). Part of the reason for the apparent reduced success rates may be that the optimal protocols for antagonistcontrolled cycles have yet to be established (Devroey et al., 2009; Huirne et al., 2007; Macklon et al., 2006). Indeed, given that there are in excess of 20 different antagonist protocols, a ‘best estimate’ protocol for use in predicted normal responders has recently been recommended (Devroey et al., 2009). However, the criteria for treatment with this protocol are restrictive, as it suggests the patient should be <35 years, have 5–9 follicles per ovary and no history of PCOS, endometriosis or previous poor response. Within European countries, this age criterion would exclude 50% and 45.3% of patients embarking on IVF and intracytoplasmic sperm injection, respectively (Nyboe Andersen et al., 2009), and therefore individualization of antagonist protocols is still required. The authors acknowledged the clear lack of evidence in certain areas including optimal starting dose, dose adjustments, day of start of GnRH antagonist and the criteria, timing and mechanism for oocyte maturation. Furthermore, some steps which, despite being intuitive have limited supportive evidence, may still be amenable to further optimization. For example, timing of the commencement of stimulation by either FSH alone or alternatively human menopausal gonadotrophin (HMG) has only been addressed in relatively small studies. The challenge ahead for clinicians may be better identification of the patient’s phenotype prior to stimulation in order to individualize and optimize treatment in their first IVF cycle.

Alternatives to one size fits all There are now a multitude of options for ovarian stimulation in IVF (Table 1). However, none of the currently available protocols are universally established by accepted usage or general agreement, and therefore conventional ovarian stimulation for all patients no longer exists. Furthermore, additional modifications have been proposed in ovarian stimulation to improve response in women showing suboptimal response to ‘conventional’ protocols. These have included altered timing and dose of agonist administration (Cedrin-Durnerin et al., 2000; Detti et al., 2005), various combinations of gonadotrophins in particular the addition of LH (Mochtar et al., 2007), and pretreatment with testosterone (Balasch et al., 2006; Fa ´bregues et al., 2009), dehydroepiandrosterone (DHEA) (Barad and Gleicher, 2006), human chorionic gonadotrophin (HCG) (Beretsos et al.,

Summary of available conventional protocols for ovarian stimulation.

Protocol

Agent

Long, short and microflare protocols

GnRH agonists and recombinant FSH, HMG, recombinant FSH plus recombinant LH and other adjunctive agents GnRH antagonists and FSH, HMG, FSH plus LH and other agents such as clomiphene citrate No GnRH analogues and FSH, HMG and FSH plus LH

Standard, mild and modified natural cycle protocols Minimal and natural cycle protocols

GnRH = gonadotrophin releasing hormone; HMG = human menopausal gonadotrophin.

Ovarian stimulation and IVF 2009), oestrogen (Fanchin et al., 2005), growth hormone (Kolibianakis et al., 2009) and letrozole (Lossl et al., 2008). One area which has received a great deal of attention is the management of women who have poor response to conventional treatments in the first stimulation cycle. Although there is a lack of uniform definition of ‘poor response’, which can range from oestradiol concentrations less than 800–900 pg/ml to a small number (3, 4 or 5) of mature follicles, to date there is no single approach which is accepted to improve clinical outcomes (Shanbhag et al., 2007; Weissman and Howles, 2009). For many fertility physicians, the conventional approach in poor responders is to simply increase the gonadotrophin dose. The use of high doses of gonadotrophins (>300 IU FSH per day) in an individual with a limited number of antral follicles is likely to have no impact upon response as all FSH-sensitive follicles will be recruited by normal or excessive doses (Klinkert et al., 2005a). Furthermore there is no evidence that oocyte quality will be enhanced and so it is difficult to identify a hypothesis explaining how the presence of additional exogenous gonadotrophins may be beneficial. Additionally, a similar situation could well apply for oocyte donors. In a recent randomized study, Rubio et al. (2010) concluded that in high-responder donors, a decrease in the FSH dose may improve fertilization rates and embryo quality. They therefore argued that treatment should be individualized using the ‘minimal effective dose’ for an optimal IVF outcome in each patient and donor.

The role of LH Whilst it is clear that there is no absolute requirement for LH in the exogenous gonadotrophin used for ovarian stimulation, potential advantages in definable situations are possible, but they remain to be systematically investigated. There is no consensus on the threshold concentration of endogenous LH required for optimal ovarian stimulation. Many efforts have been made to define the minimum LH threshold value by measuring serum LH concentrations during ovarian stimulation with FSH alone, but these attempts have proved ineffective (Cabrera et al., 2005). Other studies have found inconsistent predictive results from low serum concentrations of LH in IVF cycles using a GnRH agonist (Balasch et al., 2001) and conflicting predictive results from high and low LH concentrations in GnRH antagonist cycles (Kolibianakis et al., 2003, 2004). LH activity can currently be derived from HMG preparations, HCG, recombinant LH and recombinant HCG. Most of the meta-analyses comparing pregnancy and live-birth rates of HMG with FSH have found non-significant differences. However, some authors (Al-Inany et al., 2008; Coomarasamy et al., 2008) have each found higher live-birth and pregnancy rates from cycles stimulated with HMG compared with recombinant FSH. However, in the most comprehensive meta-analysis carried out to date including 16 studies and a total of 4040 patients (Lehert and Ezcurra, 2010), treatment with HMG resulted in fewer oocytes ( 1.54, 95% confidence intervals (CI) 2.53 to 0.56, P < 0.0001) compared with recombinant FSH and a higher total dose of HMG was necessary (mean difference, 235.46 IU/l, 95% CI 16.62 to 454.30, P = 0.03; standardized mean difference,

143 0.33, 95% CI 0.08 to 0.58, P = 0.01). The pregnancy absolute risk difference for fresh transfers was 3% (not statistically significant) and the relative risk 1.10 (not statistically significant). When adjusted for baseline conditions, the relative risk was 1.04 (not statistically significant) and absolute difference was 0.01 (not statistically significant), respectively. One other confounding factor is that the molecule of LH which accounted for the entire LH activity in the original HMG preparations was switched to HCG in the more recently available, partially purified urinary formulations. In the recent publication by Hompes and colleagues (2008), HMG resulted in a milder stimulation response, leading to a higher cancellation rate due to poor response compared with recombinant FSH, when fixed gonadotrophin doses were used in normo-gonadotrophic women. The effect of recombinant LH administration has to be seen in the context of selected groups of patients. The Nordic LH Study in unselected patients randomized on stimulation day 1 to either recombinant FSH with or without supplementary recombinant LH in a GnRH agonist protocol found no differences in ongoing pregnancy rates (Nyboe Andersen et al., 2008). One randomized trial showed significant differences according to patient age groups (Marrs et al., 2004). Implantation rates in patients under 35 years were higher (30.7%) in those receiving FSH alone than in those receiving recombinant FSH and LH (23.5%). But in those over 35 years implantation rates were higher in the LH group than in the FSH alone group (21.7% versus 15.7%), suggesting that, while younger patients seemed not to benefit, those aged 35 or over appeared to derive a benefit from supplementary LH activity. Similar results were found in a further randomized study when normo-gonadotrophic women were stimulated with either recombinant FSH or a combination of recombinant FSH and LH, with LH supplementation starting from day 8 of the cycle (Humaidan et al., 2004). Again, there was no overall difference in pregnancy rates between the two groups, but significantly higher implantation rates and reduced total FSH consumption were found in women over 35 years given supplementary LH (36.4% versus 13.3%). Therefore, while LH supplementation from day 8 appeared to have no detrimental effect on ovarian response in younger women, there did appear to be a treatment benefit in those aged over 35. Similar results were reported by Bosch et al. (2011) and Matorras et al. (2009) in populations of women aged 35–39 years undergoing ovarian stimulation. De Placido et al. (2005) observed that recombinant LH supplementation (150 IU daily) was more effective than increasing the dose of exogenous FSH in women with an initial suboptimal response. The role of HCG as a supplement to FSH in the late follicular phase – in long and short agonist and antagonist protocols – has been reviewed in a recent meta-analysis of nine studies (Kosmas et al., 2009). From the four treatment strategies defined in the analysis, HCG supplementation in the GnRH antagonist group was associated with a nonsignificant benefit in clinical pregnancy rate (odds ratio 1.54, 95% CI 0.98–2.42). A pilot study reported by Blockeel and collaborators (2009), which compared the effect of HCG supplementation exclusively in GnRH antagonist cycles, found comparable rates of oocyte yield and pregnancy in the HCG and control groups, but a reduction in FSH consumption in the former.

144 Thus, while there is no evidence that supplementation with LH activity is necessary in an unselected IVF population, it may yet be beneficial in subgroups of patients such as older women who usually need high doses of FSH.

Androgen supplementation Because androgens have a role in follicular survival before they become sensitive to gonadotrophins, and, because they appear to promote granulosa cell functions in antral follicles, androgen supplementation has been proposed as a means to both increase follicle numbers and improve their paracrine function. A rationale for associating androgens with folliculogenesis lies in the model of PCOS, where the features of excessive granulosa cell activity, abnormal follicular development and hyperandrogenaemia are present (Nardo et al., 2009a). Hickey and colleagues (2005) while showing that androgens enhance the mitogenic effect of oocytes and the growth factor GDF9, suggested that these mechanisms are also present in PCOS. Clinical studies of androgen suppression over a 6-month treatment period in PCOS have failed to demonstrate any causative role in the pathological hyper-folliculogenesis found in PCOS. The decline in both androgen and anti-Mu ¨llerian hormone (AMH) concentrations was only modest in two studies with metformin (Fleming et al., 2005; Piltonen et al., 2005), and when dexamethasone was added in a third study, there was no effect on AMH, despite a fall in androgen concentrations (Carlsen et al., 2009). Thus, while such studies indicate no effective role for androgen suppression in excessive folliculogenesis, they also give no theoretical credence to the proposal that protracted androgen treatment will improve poor ovarian reserve. Furthermore, very recent mouse data have shown that induced hyperandrogenism may impair early follicle development by increasing ovarian oxidative stress which in turn induces enhanced ovarian prostaglandin E production, increased number of T lymphocytes and decreased expression of the long isoform of the leptin receptor (Belgorosky et al., 2010). More experimental studies are required to demonstrate the direct or indirect effect of excess of androgens on follicle atresia. Some small studies have, however, suggested a benefit from androgen supplementation. Barad and Gleicher (2006) found that supplementation over 17 weeks with the weak androgen DHEA improved response to ovarian stimulation, with a significantly higher oocyte yield, number of oocytes fertilized and average embryo scores per oocyte. A study, which was presented at the ESHRE annual meeting in 2009, was performed in women with diminished ovarian reserve, as determined by circulating AMH concentrations, and found that after a minimum of 1 month’s treatment with DHEA (25 mg orally three times daily), a significant increase in AMH was achieved (Goyal et al., 2009). Subsequent IVF treatment demonstrated that those with an increase in AMH during treatment had a higher chance of pregnancy. More recently, a randomized prospective controlled trial including 33 women with reduced ovarian reserve showed a significantly higher live-birth rate in the DHEA group (75 mg daily) compared with controls (Wiser et al., 2010). It is plausible to speculate that the positive effect of DHEA

LG Nardo et al. in selected women with diminished ovarian reserve may be related to stimulation of steroidogenesis and/or orchestration of growth factors such as insulin-like growth factor (IGF)-I in the ovary. The second rationale for androgen supplementation lies in a much shorter-term concept involving the paracrine functions of antral follicles growing under the influence of gonadotrophins. Studies have found a constant dialogue exchanged between granulosa and theca cells in both steroidogenesis and growth, with androgens derived from theca cells promoting granulosa cell sensitivity to FSH (Hillier, 2001). Thus, in this context, therapeutic approaches would address improved function rather than increased follicular numbers, because the number of antral follicles present at this stage has already been determined by preceding events. Balasch et al. (2006) reported in a well-defined, albeit small study group (n = 25) of patients who had two previous cycle cancellations due to poor follicular response but having normal basal FSH, that pretreatment with transdermal testosterone (20 g/kg per day) resulted in 80% of the patients reaching oocyte recovery and achieving a clinical pregnancy rate of 30% per oocyte retrieval. In another randomized study using short-term transdermal testosterone (2.5 mg/day), Massin et al. (2006) have found little encouragement for a beneficial effect on follicles, metaphase II-retrieved oocytes or high-quality embryos. However, Fa ´bregues et al. (2009) concluded in a recent controlled study that pretreatment with transdermal testosterone in patients with normal baseline FSH, improves the ovarian sensitivity to FSH, as shown by lower incidence of low response and a higher number of women reaching egg collection in the treatment group as compared with controls. More recently, a prospective randomized double-blind placebo-controlled crossover study investigating the effect of exogenous testosterone pretreatment in women aged between 38–45 years on ovarian folliculogenesis and steroidogenesis found increased testosterone concentrations but no effect on follicles greater than 10 mm in diameter (Sipe et al., 2010). Indeed, it has already been well demonstrated that peripheral androgens have little or no direct impact at the follicular level, where local concentrations are some 1000-times higher than in the peripheral circulation. Any effect from short-term administration, therefore, is likely to be by a more indirect mechanism. Two approaches have so far been explored: one to promote theca-cell activity (with LH or HCG administration) and the other to increase intrafollicular androgen concentrations before FSHmediated recruitment (using aromatase inhibitors). The first strategy was investigated in a study of down-regulated IVF patients randomized to either 1 week’s pretreatment with recombinant LH or to continuing down-regulation prior to ovarian stimulation (no pretreatment) (Durnerin et al., 2008). While results showed no indication of any quantitative effect of the LH pretreatment in terms of follicular sensitivity to FSH or ovarian hormone secretions, there was a non-significant increase in oocyte yield and a significant increase in normal embryo yield (from an average of 5.1 to 7.0 per patient). The increased LH activity in the treatment group was associated with an increase in small antral follicle count at the start of FSH treatment. Similarly, the proportion of antral follicles developing to 14 mm was

Ovarian stimulation and IVF higher in the patients given the aromatase inhibitor letrozole and HCG before ovarian stimulation as androgen priming, and the increase in follicular fluid androgen concentrations was confirmed after egg collection (Lossl et al., 2008). This study however failed to demonstrate significant differences in the number of oocytes retrieved and the number of top-quality embryos.

Growth hormone supplementation Growth hormone modulates the effect of exogenous gonadotrophins on granulosa cells by up-regulating the intra-ovarian synthesis of IGF-I, which in turn leads to augmentation of aromatase activity, oestrogen production, stimulation of follicular development and oocyte maturation (Blumenfeld and Amit, 1996; Yoshimura et al., 1996). A recent Cochrane meta-analysis of randomized controlled trials showed no difference in outcome measures and adverse events when growth hormone was used routinely in IVF programmes. However, there appears to be a statistically significant difference in live-birth rates favouring the use of growth hormone in known poor responders without increasing the adverse events (Duffy et al., 2010). Limitations of the meta-analysis were the few trials included, their small sample size and the diverse definitions of poor response used by the different authors. Therefore, until further evidence is available the present data needs to be interpreted with caution.

Patient selection A randomized trial (Heijnen et al., 2007) has already shown that the patient’s goal from assisted conception treatment is a healthy live birth. Throughout the last couple of decades it has been clear that patients respond differently to ovarian stimulation, yet its objective has remained the same – optimization of response and outcomes whilst minimizing the risks. The latter has been conventionally determined by the number of oocytes retrieved in a treatment cycle (Popovic-Todorovic et al., 2003), but such a measure seems inappropriate in countries which impose legal constraints on the number of oocytes available for fertilization or indeed on embryo freezing, and also when an excessive response puts the patient’s wellbeing at risk. With regulatory and peer demands for reducing multiple pregnancies, and patient desire for more effective IVF, the challenge to predict response to ovarian stimulation in each patient has become even greater. Two decades of trial-and-error studies have suggested that chronological age, basal serum FSH concentrations, body mass index and the number of antral follicles may all affect and predict outcome (Howles et al., 2006; Klinkert et al., 2005b). When these four factors were modelled into an algorithm to determine individual FSH starting dose as a reflection of ovarian response, a median of 9.0 oocytes were retrieved from the five possible dose groups (75–225 IU), all within an expected range of ‘normal response’ (Olivennes et al., 2009). Only two patients (out of 161) developed severe OHSS, whilst 14.3% of cycles were cancelled for inadequate response. The high cancellation rate in this pilot study

145 (Olivennes et al., 2009) was similar to that reported in a randomized trial of mild IVF (Heijnen et al., 2007). This concept therefore addressed individualized ovarian stimulation through simply modifying the FSH dose. Other components may include source of FSH and LH blockade strategy. It is still debatable whether standard stimulation algorithms are better than years of direct clinical experience. The added predictive value of ovarian response tests as reflected in measures of basal FSH, inhibin B, oestradiol, ovarian volume and vascular flow, antral follicle count and AMH has been explored in a large number of studies and meta-analyses. AMH can be measured on a random plasma sample at any point in the menstrual cycle and is highly reproducible (van Disseldorp et al., 2010) – although detailed studies looking at normative data for inter- and intra-cycle variability in different ethnic populations remain to be performed. Data in the literature suggest that AMH is especially correlated with ovarian response (Nardo et al., 2009b; Nelson et al., 2007). Many case–control and cohort studies have shown marked concordance in plasma concentrations with women at risk of extremes of response (La Marca et al., 2010). Furthermore, a high AMH correlates significantly with oocyte yield, good-quality embryos and live birth (Majumder et al., 2010; Nelson et al., 2007). A prospective study of 340 first IVF/intracytoplasmic sperm injection cycle patients whose AMH and FSH concentrations were measured at baseline showed that AMH was a better predictor of live birth and oocyte yield than chronological age and FSH separately, and as such would better help determine the individualization of dose and strategy prior to ovarian stimulation (Nelson et al., 2007). The authors proposed that women with an AMH concentration of 1–5 pmol/l are at risk of either cycle cancellation or poor response, those with concentrations of 5-15 pmol/l have a high probability of a normal and safe response to a standard long course down-regulation strategy, and those with concentrations of >15 pmol/l are at risk of excessive responses thus requiring a protocol mindful of OHSS risk – that is with antagonist control and modest FSH doses. The risk of OHSS is substantial when AMH concentrations are >25 pmol/l. This study, as well as 14 others included in a recent metaanalysis (La Marca et al., 2010), collectively suggest that AMH correlates with oocyte yield better than chronological age, ovarian volume, FSH, oestradiol and inhibin B concentrations on day 3. The assessment of ovarian performance by AMH prior to entering the first cycle of ovarian stimulation may be a useful approach to individualize treatment, optimize the chance of live birth and allow the clinician to adapt a stimulation strategy aimed at minimizing risks at the extremes of response (Nelson et al., 2009).

Conclusions The ability of women to respond to ovarian stimulation regimens is highly variable and although it declines with age, age alone is a poor indicator. The prediction of extremes of response and the irreversibility of decreased ovarian reserve have been one of the most debated issues of IVF treatment in the last decade. Entering ovarian stimulation without knowledge of individual ovarian potential is unacceptable owing to the ethical, psychological, financial

146 and health consequences of extremes of response. Nevertheless, there are differences in the practical approach to stimulation depending on the country, demographics, funding stream and existing guidelines. Several authors have attempted to challenge the given limitations by modifying conventional stimulation protocols according to patients’ characteristics, thus individualizing ovarian stimulation, while others have decided to adopt standard patient-friendly stimulation protocols with low doses of gonadotrophins. Whilst there is convincing evidence that the incidence of excessive ovarian response associated with a high risk of OHSS and cycle cancellation can be reduced significantly by ovarian stimulation treatment with low-dose gonadotrophins and GnRH antagonists, the management of women with low ovarian reserve and poor ovarian response remains controversial. Simply increasing the dose of gonadotrophins may not be optimal to stimulate the development of the follicle cohort which has already entered the process of recruitment by this time. Therefore, priming ovarian function prior to commencing ovarian stimulation may prove to be a sensible approach, although the available data need to be confirmed and, as such, patients should be made aware of the still limited evidence. It has emerged that some exogenous agents – LH, HCG, testosterone, DHEA and aromatase inhibitors – contribute to the paracrine regulation of the early stages of follicular maturation and atresia, and may play a role in controlling ovarian response in women with suboptimal ovarian performance. Out of all the options, LH administration in older women as well as in those with evidence of compromised ovarian performance irrespective of chronological age, may improve cycle outcomes. Androgens may also have a beneficial role in selected patient types as unlike FSH they affect the predevelopment stages of the follicle’s cycle. Research in the androgen-mediated follicular dynamics is necessary. Determining the daily dose, time and duration of androgen supplementation as well as other agents may be crucial to adequately stimulate folliculogenesis and individualize treatment.

Acknowledgements The Manchester expert meeting ‘Striving to improve Controlled Ovarian Stimulation in ART’, 12 November 2009, was supported by an unrestricted educational grant from Merck Serono Ltd, UK, an affiliate of Merck KGaA, Darmstadt, Germany.

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