Scientific Highlights: First world conference on luteinizing hormone in ART: Landing in Asia Pacific

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1 This EXCEMED conference followed on from the First world conference on luteinizing hormone (LH) in ART, which took place in Naples in May Bringing the topic of LH to Asia Pacific provided an opportunity for content to be updated in this rapidly evolving field. The role of recombinant LH in ART continues to be explored in the laboratory and clinic, further characterizing the relevance of, and evidence base, regarding LH use in controlled ovarian stimulation (COS) protocols. Summaries of the Bangkok presentations are included in these highlights. Contents The history of POR: Is it time to turn the page? Ovarian reserve, euploidy rates and ovarian sensitivity: three actors for one movie From POR to low prognosis concept: a new proposed stratification by POSEIDON Working Group How many oocytes are needed for one euploid embryo? COS strategies to increase oocyte number/quality DuoStim: the alternative of oocytes/embryos accumulation programs The rationale for the use of LH drugs during COS: from basic science to clinical practice Which POSEIDON groups may benefit from LH supplementation? Personalized luteal phase support. The future in ART? The history of POR: Is it time to turn the page? There is an urgent need to refine international criteria for poor ovarian response (POR), said Dr Sandro C. Esteves (Campinas, Brazil). Improving the criteria for POR, with a stratification that incorporates prognosis for pregnancy, may help to improve ART success rates for women with this condition. By improving how POR is classified, we can focus on developing better therapeutic solutions for assisted reproduction. Previous classification systems for POR, such as the Bologna Criteria (ESHRE 2011), have not properly considered important facts such as ovarian sensitivity and oocyte quality. These factors need to be better distinguished in future POR criteria, said Dr Esteves. Although the Bologna criteria were important for standardizing the definition of POR (Figure 1), these criteria are limited in value, in both research (where they do not eliminate clinical heterogeneity within the POR population), and in clinical practice (where they do not differentiate well enough to improve treatment selection in individuals with POR).

2 Figure 1: The Bologna (2011) criteria for poor response. There is growing evidence that it is time to improve these criteria, to take account of oocyte number and quality. This slide featured in a later presentation by Dr Humaidan By focusing on advancing age, previous evidence of POR and biomarkers of abnormal ovarian reserve, Bologna and other criteria for POR are unable to identify consistently a homogeneous population with similar clinical outcomes (Table 1). The problems are that: Women with POR may be draw from several subgroups, with diverse baseline characteristics, such as: High biological variability (e.g. aged < 35 years, low ovarian reserve, previous POR episode; aged < 35 years, normal ovarian reserve, two previous POR episodes; aged 40, normal ovarian reserve, one previous POR) Age-related differences in oocyte quality Consequently, the Bologna criteria do not account for differences in pregnancy prognosis within the POR subgroups, although Dr Esteves acknowledged that it is unclear whether any criteria for POR eliminate the clinical heterogeneity in such populations. In addition, Bologna and other previous criteria cannot distinguish between patients with reduced ovarian reserves and patients with inherent ovarian resistance (e.g. genetic polymorphisms) that reduce their response to gonadotropins. Dr Esteves presentation led the way for others at the conference to discuss possible improvements to the criteria for POR.

3 Table 1. Bologna criteria for POR have been applied successfully in only a few studies Ovarian reserve, euploidy rates and ovarian sensitivity: three actors for one movie The correct management of female infertility is a challenging drama that involves three lead actors: ovarian reserve, euploidy rates and ovarian sensitivity to gonadotropins. Dr Carlo Alviggi (Naples, Italy) called for better definitions of specific subgroups when ovarian reserve or sensitivity, or euploidy, is involved. He described the issue as a poor prognosis concept rather than a POR concept, and described the following clinical and research needs: Adopting practical endpoints for individual women (e.g. how many oocytes do we need for this woman of X age to have at least one euploid embryo?) Identifying new strategies for increasing the number of oocytes/embryos (not merely drug/analogue regimens) Variability in the patient population means that no single COS protocol will work in women with poor pregnancy prognosis. Instead, personalized infertility management is required, in which factors such as ovarian reserve and ovarian sensitivity to exogenous gonadotropin are evaluated. Ovarian ageing can be subdivided into follicular depletion (limited ovarian reserve), aneuploidy (reduced ovarian/oocyte quality) and reduced mitochondrial activity. 3

4 Ovarian sensitivity focuses on the ovarian response to gonatotropins in COS, and is classified as poor in women who are hyporesponders to follicle stimulating hormone ([FSH]; follicle output ratios ~30%). FSH sensitivity is observed in 15% of women with normal ovarian reserve, in whom oocyte retrieval and oestradiol production is adequate but there is an increase in the cumulative FSH consumption (dose and duration of stimulation). Hyporesponse is now believed to be related to genetic characteristics, such as FSH-R Ser 680 genotype and FSH sensitivity. Dr Alviggi outlined how knowledge of factors that affect COS success/failure has evolved (Figure 2). He added that it is now important to consider whether the Bologna criteria for POR take adequate account of these prognostic factors, now that the roles of FSH and LH sensitivity are clearer (Figure 3). Figure 2. Evolution of factors that affect COS failure or success role of FSH (and LH) sensitivity Figure 3. Strengths and limitations of the Bologna criteria, regarding ovarian ageing and sensitivity

5 From POR to low prognosis concept: a new proposed stratification by POSEIDON Working Group The POSEIDON Working Group aims to better define pregnancy prognosis for women with POR. Professor Peter Humaidan (Aarhus, Denmark) described how the POSEIDON stratification characterizes four groups of poor responders (Figure 4). Unlike previous criteria, POSEIDON includes the woman s ovarian reserve and age. Figure 4. The four groups of women described by the POSEIDON Working Group, in their stratified definition of women with POR Professor Humaidan reviewed therapeutic options for POR, some of which have no effect on clinical pregnancy rate (e.g. increasing the FSH dose, natural cycle IVF), and some of which require more data (e.g. DHEA treatment, transdermal testosterone, recombinant LH). The results of ongoing or better-quality studies, with subgroups evaluated according to the POSEIDON stratification, will help to better answer these questions, thus improving the ART prognosis for women with POR. The group is now working to identify matching protocols and regimens, such as the example shown in Figure 5. Figure 5. Possible treatment options for women with poor reserve and poor quality; POSEIDON is developing protocols for each of four groups of women with POR 5

6 How many oocytes are needed for one euploid embryo? When estimating the number of oocytes needed for one euploid embryo transfer it is important to remember three things: Oocyte quantity and oocyte quality are not the same Normal (euploid) embryo output varies among populations undergoing IVF Transfer of a euploid embryo practically eliminates the age-related decline in implantation rate Computing four common IVF parameters %MII, &2PN, cleavage (D3) or blastocyte formation rate, and embryo euploid rates provides a reasonable estimate of the number of oocytes required for achieving one euploid embryo. Dr Sandro C. Esteves (Campinas, Brazil) explained these calculations in practical terms: a generalized estimate can be obtained by inputting data into the following formula (Figure 6): Figure 6. Formula for estimating number of oocytes required to achieve one euploid embryo transfer He added that, although this approach needs to be fully validated, the concept of combining quantitative and qualitative parameters should help in the quest to individualize ART and set appropriate expectations, both for clinicians and their patients. Clinics should use their own databases to extract the information necessary to make the calculations, to improve the local reliability of estimates. Maternal age, paternal age and sperm source/quality will also likely affect the accuracy of any calculation. When the mother is aged >35 years and has POR, to decrease the time to pregnancy Dr Esteves advocates the triad of: Evaluate properly Give a fair estimate of the outcome Develop a time-limited treatment plan This strategy is aligned with the POSEIDON Working Group proposal for better stratification of poor responders to IVF regimens, to increase the potential for retrieving the optimum number of oocytes necessary for at least one euploid embryo transfer. COS strategies to increase oocyte number/quality Fifteen is the maximum number of oocytes to retrieve, to optimize the likelihood of a live birth. Oocyte/embryo quality declines with age, but not with the number of oocytes/embryos achieved after COS. Professor Peter Humaidan (Aarhus, Denmark) said that the optimum COS protocol should focus on

7 retrieving sufficient oocytes to likely lead to one euploid embryo transfer, without increasing the risk of ovarian hyperstimulation syndrome (Figure 7). Figure 7. Advice on the optimum number of oocytes to maximize the IVF pregnancy rate Research has corroborated the importance of distinguishing between high- and low-responder patients with high late follicular progesterone levels: the former, not the latter has an excellent reproductive outcome. Whether poor embryo quality, rather than reduced endometrial receptivity, is the reason for the poor outcome remains unclear. DuoStim: the alternative of oocytes/embryos accumulation programs The double stimulation approach (DuoStim) could increase the number of available euploid blastocysts within a single menstrual cycle. This one-round double stimulation protocol may increase the likelihood of achieving competent oocytes and live births in those with a poor pregnancy prognosis following exogenous gonadotropin (e.g. women in Groups 3 and 4 in the POSEIDON stratification). Dr Carlo Alviggi (Naples, Italy) described DuoStim, which consists of both follicular phase (FP) and luteal phase (LP) stimulations within a single menstrual cycle (Figure 8). 7

8 Figure 8. DuoStim may be a useful strategy for women with POR, with poor pregnancy prognosis DuoStim follows the principle that follicles developing during the luteal phase may have the potential to ovulate in the presence of a LH surge, offering improved possibilities for ovarian stimulation. Two or three follicular waves have been observed in ultrasonographic studies taken during the intraovulatory period. Such waves are characterized by an increase, then decrease, in the number of 5mm follicles, as two follicles reach 6mm. Existing antral follicles in the luteal phase enable ovarian stimulation. Luteal-phase stimulation is already used in cryopreservation strategies, such as in women requiring emergency fertility preservation. In Group 3 or 4 patients (POSEIDON), oocyte/blastocyst accumulation is an option, and the DuoStim strategy helps to maximize the number of oocytes per menstrual cycle in these women, while taking account of the woman s ovarian reserve. Figure 9 shows the mean number of oocytes needed. Figure 9. Mean number of oocytes needed to optimize the likelihood of a euploid blastocyst

9 The rationale for the use of LH drugs during COS: from basic science to clinical practice Using LH during COS may offer a corrective measure for specific subgroups of women with history of unsuccessful ART. Dr Sandro C. Esteves (Campinas, Brazil) uses LH in COS for women with expected POR (i.e. those with abnormal markers of ovarian reserve), hyporesponders, and those aged >35 years undergoing GnRH antagonist cycles. He advocated treatment with a 2 : 1 ratio of recombinant-hfsh ( miu/day) plus recombinant-lh ( miu/day), from Day 1 of stimulation. This regimen has achieved live birth rates in 63% of women in POSEIDON Group 1, and 41% in POSEIDON Group 2 women (300 cycles). Similarly, it has achieved live birth rates following antagonist cycles in 37% of women aged and in 22% of those aged (1229 cycles). In women with expected POR, live birth rates were 35% for those in POSEIDON Group 3 and 16% (rising to 33% with DuoStim/Accuvit regimens), in POSEIDON Group 4 women. COS induces a status of relative LH deficiency in all women; this is particularly problematic for older women, and women of any age with defective endogenous LH or impaired steroidogenesis. A low LH level may contribute to a decrease in the number of retrieved oocytes; it may increase the likelihood of poor oocyte or embryo quality and low pregnancy rates, said Dr Esteves. The LH window concept proposes that, in the absence of a serum LH of miu/l, oestradiol production is insufficient for follicular development, endometrial proliferation and corpus luteum formation (Figure 10). Figure 10: Low LH levels are seen with all COS protocols. Is LH administration therefore necessary, to increase the likelihood of successful ART? 9

10 Certainly, LH is crucial for sustaining FSH-dependent granulosa activities, and both recombinant hlh and hcg exert LH activity. Three available gonadotropin preparations containing LH: mmg/hp-hmg Recombinant LH Recombinant FSH plus LH (fixed 2 : 1 ratio). Better cycle outcomes are reported with recombinant LH versus hmg in women with profound LH deficiency (WHO I) undergoing COS. Several in vitro studies confirm that recombinant LH and hcg yield LH activity through different mechanisms: hcg is predominantly prosteroidogenic and potentially pro-apoptotic; recombinant LH is predominantly a pro-growth, differentiation and survival factor. Recombinant LH administered during COS has a stimulatory effect on FSH-dependent granulosa cell activities and steroidogenesis. Guidelines support LH use in COS protocols for women in POSEIDON groups 1 or 2 (i.e., those with sufficient ovarian reserve parameters but have unexpected poor or suboptimal ovarian response to FSH monotherapy). Recombinant LH should commence at the mid follicular phase to rescue the ongoing cycle, or at stimulation day 1 in a subsequent cycle. LH use is also appropriate for women aged years in GnRH antagonist cycles, where it should start on Day 1, if OCP are given before stimulation. There is no evidence that recombinant LH, or any gonadotropin containing LH activity, is beneficial for poor responders undergoing COS after pituitary down-regulation with GnRH agonists, or normoresponsive women aged <35 years, irrespective of the GnRH analogue. Which POSEIDON groups may benefit from LH supplementation? The POSEIDON stratification may help to personalize ART in women with POR. Dr Carlo Alviggi (Naples, Italy) gave practical examples of how POSEIDON introduces two new categories of impaired response to exogenous gonadotrophin (suboptimal or hyporesponse). This more precise classification of POR may help to improve ART outcomes by better tailoring COS protocols to suit individual situations. Dr Alviggi explained how choice of GnRH analogue regimen, detection of polymorphisms of gonadotropins and their receptors, tailoring the FSH start dose and using LH supplementation may be improved when the POSEIDON stratification is applied. POSEIDON stratifies four groups of women have a poor COS prognosis due to POR (see Figure 4): Group 1 includes women with hyporesponse: rhlh administration may be effective in rescuing the number of follicles/oocytes, and achieving embryo competence, if hyporesponse is identified in days 5 8 of COS.

11 Group 2 includes older women with normal ovarian reserve, who likely have reduced androgen production: administering LH significantly improves implantation rates, although there is no evidence for improvement in ongoing pregnancy or live birth rates. The efficacy of rlh in Groups 3 and 4 POSEIDON (women with low ovarian reserve) is under evaluation (ESPART subgroup analyses). Personalized luteal phase support. The future in ART? A growing body of scientific evidence supports personalized luteal phase support, in fresh and in frozen embryo transfer (FET) cycles. Professor Peter Humaidan (Aarhus, Denmark) explained why luteal phase support is mandatory for all women undergoing IVF/ICSI. He also emphasized how the new personalized approach is being suggested as an improvement on standard (fixed regimen) recommendations. Monitoring mid-luteal progesterone levels may help to increase implantation/ongoing pregnancy rates in both fresh IVF/ICSI and FET cycles. Lower cut-off values for mid-luteal progesterone (prior to implantation) in serum are needed to support early implantation. This threshold is ~ nmol/l in fresh and FET cycles; the progesterone ceiling is >440 nmol/l in fresh cycles (Figure 11). Figure 11: Luteal progesterone and ongoing pregnancy, following GnRHa trigger administration No FET regimen shows superiority with regard to reproductive outcome. True natural FET cycles benefit from vaginal progesterone supplementation, which starts after embryo transfer. Modified natural FET cycles require ultrasound monitoring. Luteal phase support with progesterone appears to be unnecessary, due to the luteotrophic effect of hcg. HRT-FET cycles are convenient for monitoring and scheduling purposes. 11