REVIEW published: 11 September 2019 doi: 10.3389/fendo.2019.00614 Management Strategies for POSEIDON Groups 3 and 4 Thor Haahr 1,2*, Carlos Dosouto 3,4 , Carlo Alviggi 5,6 , Sandro C. Esteves 1,2,7,8 and Peter Humaidan 1,2 1 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, 2 The Fertility Clinic Skive, Skive Regional Hospital, Skive, Denmark, 3 Hospital de la Santa Creu i Sant Pau- Fundació Puigvert, Obstetrics, Gynecology and Reproductive Medicine, Barcelona, Spain, 4 Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain, 5 Department of Neuroscience, Reproductive Science, and Odontostomatology, University of Naples Federico II, Naples, Italy, 6 Consiglio Nazionale Delle Ricerche, Istituto per L’Endocrinologia e L’Oncologia Sperimentale, Naples, Italy, 7 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil, 8 Department of Surgery, University of Campinas, Campinas, Brazil In the POSEIDON classification, patients belonging to groups 3 and 4 share the same common feature of a poor ovarian reserve which independently of age renders them at high risk of a poor reproductive outcome. Overall, POSEIDON groups 1–4 Edited by: Katja Teerds, constitute approximately 47% of patients attending assisted reproductive technology Wageningen University, Netherlands (ART) treatment. With the increasing delay in childbearing, POSEIDON group 4 seems Reviewed by: to increase in numbers now in some centers constituting more than 50% of the total Matheus Roque, Clínica Origen, Brazil POSEIDON population, whereas group 3 patients constitute approximately 10%. Both Hakan Yarali, POSEIDON groups 3 and 4 patients require special attention as regards pre-treatment Anatolia IVF Center, Turkey strategy, ovarian stimulation, adjuvant treatment, and ovulation trigger strategy in order Antoine Abu Musa, American University of to optimize the probability of having at least one euploid blastocyst for transfer. Although Beirut, Lebanon more evidence is needed, recent advances seem to have increased the reproductive *Correspondence: outcomes in the poor prognosis patient. The key to success is individualization in all Thor Haahr thohaa@rm.dk steps of ART treatment. Herein, we review the recent evidence for the management of POSEIDON groups 3 and 4. Specialty section: Keywords: poor ovarian response, Bologna criteria, POSEIDON criteria, controlled ovarian stimulation, blastocyst, This article was submitted to pregnancy, ART calculator Reproduction, a section of the journal Frontiers in Endocrinology PREVALENCE OF POSEIDON GROUPS 3 AND 4 Received: 18 March 2019 Accepted: 23 August 2019 The POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) Published: 11 September 2019 population constitutes 47% of patients referred to Assisted Reproductive Technology (ART) Citation: treatment (1). POSEIDON group 3 constitutes 10% whereas POSEIDON group 4 constitutes Haahr T, Dosouto C, Alviggi C, 55% (1). In a group of Bologna criteria poor ovarian response (POR) patients, the prevalence of Esteves SC and Humaidan P (2019) Management Strategies for POSEIDON group 3 and 4 patients was recently reported to be 24% (13/54) and 76% (41/54), POSEIDON Groups 3 and 4. respectively (2). As these patients have a high risk of ending up with no high quality embryos Front. Endocrinol. 10:614. for transfer (3), they often undergo repeated numbers of ovarian stimulations with a subsequent doi: 10.3389/fendo.2019.00614 increase in both physical, emotional and financial cost. In this review, we add to the prior work Frontiers in Endocrinology | www.frontiersin.org 1 September 2019 | Volume 10 | Article 614 Haahr et al. Management of Poor Prognosis Patients considering POSEIDON classification (4–6) by giving In this aspect, and while waiting for better evidence, this recommendations for clinical management and further research review may help clinicians plan how to most optimally manage in POSEIDON groups 3 and 4. the poor prognosis patient which is an integral part of daily clinical life. EVIDENCE FOR MANAGING POSEIDON GROUPS 3 AND 4 PATIENTS MEASURE OF SUCCESS Although studies in POSEIDON groups 3 and 4 patients According to the POSEIDON concept, the measure of success are emerging (7, 8), there are currently very few prospective is to increase the probability of having at least one euploid studies comparing different treatment strategies. Hence, the blastocyst for transfer in the individual patient (6). Recently, present suggestions for clinical management is mainly based a predictive tool so-called “ART Calculator” was launched on evidence from patients labeled with POR. In this aspect, to estimate the number of oocytes needed to have at it is important to distinguish between studies performed least one euploid blastocyst for transfer, available on http:// before and after the introduction of the Bologna criteria for www.members.groupposeidon.com/Calculator/. This calculator POR. Prior to the Bologna criteria, studies used multiple provides the estimation mentioned above based on a number definitions of POR, introducing heterogeneity and subsequently of predictors such as female age and type of sperm, which a poor clinical value of the reported results, in particular were found to be relevant concerning blastocyst euploidy, see those of meta-analyses (9). In the latest Cochrane review Figure 1 (1, 13). Thus, using mathematical equations and the from 2010 in POR management, it was reported that there age-related probabilities of a blastocyst being euploid per mature is no evidence to support one particular intervention (10). oocyte as a function of sperm source, the ART calculator makes However, Cochrane meta-analyses may not be the optimal tool two types of predictions automatically, one using pre-treatment to evaluate treatment strategies while such strategies are still information to estimate the minimum number of mature oocytes undergoing development and additional fine tuning (11, 12). to achieve at least one euploid blastocyst, and another based on FIGURE 1 | Online calculator to determine the minimum number of mature oocytes required to obtain at least one euploid blastocyst for transfer in infertile patients undergoing IVF/ICSI cycles. The figure shows how the online calculator can be used in an office-based setting. Pre-treatment, clinicians should input the patient age and the sperm source to be used for IVF/ICSI. If the option “Testicle” is marked, then the type of azoospermia should be also defined. The probability of success is set by the user and indicates the chance of having ≥1 euploid blastocyst when the predicted number of mature oocytes is achieved. Its complement is the risk, that is, the chance of having no (zero) euploid blastocysts when the predicted number of oocytes is achieved. Once the button “calculate” is pressed, a text box will pop-up on the right side of the screen, indicating the predicted minimum number of mature oocytes needed for obtaining at least one euploid blastocyst, with its 95% confidence interval (reprinted with permission of the author). Frontiers in Endocrinology | www.frontiersin.org 2 September 2019 | Volume 10 | Article 614 Haahr et al. Management of Poor Prognosis Patients the actual number of mature oocytes collected/accumulated to that natural cycle IVF might be an option for the POR patient estimate the chances of having a euploid blastocyst using that (14, 15). However, abundant evidence does not support this oocyte cohort for IVF/ICSI, see Figure 2. Apart from guiding concern neither in young oocyte donors nor in PGS IVF-ET the clinician in individualized management, the ART calculator patients (16–19). Moreover, natural cycle IVF results in extremely constitutes an ideal tool to counsel patients about their prognosis low live birth rates in the POR patient with a reported live when embarking on ART treatment, and subsequently, at the birth rate per cycle of only 2.6% and a cumulative live birth time of oocyte retrieval where some patients might be counseled rate of only 7% after six natural IVF cycles in Bologna POR to go directly to a luteal phase stimulation in order to increase patients (20). Similarly, extremely low live birth rates after natural the chances of having at least one euploid blastocyst for transfer cycle IVF have been corroborated by others (21). In contrast (13). As an example, the ART calculator estimates that at the largest RCT aligned with the ESHRE Bologna POR criteria least 6–9 and 10–15 mature oocytes are needed to obtain one reported a live birth rate per cycle of 11% using a combination euploid blastocyst for transfer in POSEIDON groups 3 and 4 of a long gonadotropin releasing hormone agonist (GnRHa) patients aged 33 and 36 years-old, respectively, assuming a 90% down-regulation protocol and daily gonadotropin dosing with probability of success in the estimations when ejaculated sperm is 300 IU recombinant FSH and 150 IU recombinant LH (22). used for IVF/ICSI. Hence, planning of the most optimal ovarian Recently, combining follicular and luteal phase stimulation in the stimulation regimen is of paramount importance to achieve same ovarian cycle two trials reported ongoing pregnancy rates the highest success rate. above 20% per DuoStim cycle in poor prognosis patients (2, 23). Thus, ovarian stimulation rather than natural cycle should be the OVARIAN STIMULATION IN POSEIDON preferred first line treatment in the poor prognosis patient with a poor ovarian reserve. GROUPS 3 AND 4 Natural Cycle or Stimulation With Stimulation Protocol Exogenous Gonadotropins A meta-analysis in non-Bologna criteria POR patients explored Previously, some authors expressed concern that stimulation the optimal GnRH analog treatment (24). From this analysis, it per se would increase embryonic aneuploidy rates, suggesting was concluded that there was no significant difference in clinical FIGURE 2 | ART online calculator. The figure shows how the online calculator can be used post-treatment, i.e., when fewer than the predicted number of mature oocytes are obtained after one or more oocyte retrieval cycles. Clinicians should input the pre-treatment information and the actual number of mature oocytes collected or accumulated. The probability of success is set by the user; it reflects the chance that the estimation is correct given the number of oocytes input. Once the button “calculate” is pressed, a text box will pop-up on the right side of the screen, indicating the predicted probability of achieving ≥1 euploid blastocyst with the number of mature oocytes available (reprinted with permission of the author). Frontiers in Endocrinology | www.frontiersin.org 3 September 2019 | Volume 10 | Article 614 Haahr et al. Management of Poor Prognosis Patients pregnancy rates comparing the long GnRHa down-regulation follicular phase stimulation and blastocysts obtained from luteal protocol to the GnRH antagonist protocol, although the trend phase stimulation, 39.5% (32/81) and 49.4% (41/83), respectively favored the long GnRHa down-regulation protocol. Later, a study (23). Although the study excluded patients with no response published in Bologna POR patients reported that the long GnRH to DuoStim (43/353), an ongoing pregnancy rate per DuoStim agonist protocol, albeit non-significantly, increased the number cycle of 20.7% (73/353) in POSEIDON group 4 patients of mature oocytes by one oocyte as compared to the GnRH can be considered highly successful in this difficult patient antagonist protocol (25). Moreover, the cancellation rate was group. Another recent study used the combined advantages of significantly lower for the long GnRHa protocol. The biological Corifollitropin alfa and Duostim in Bologna criteria patients plausibility for this finding may be follicular synchronization (N = 54), 24% (13/54) and 76% (41/54) were POSEIDON group obtained after downregulation, which is paramount for the poor 3 and 4 patients, respectively. In this study, authors reported an ovarian reserve patient as this patient usually has an increased ongoing pregnancy rate per DuoStim cycle of 20.4% (11/54) (2). late luteal FSH level, promoting early recruitment of the leading Hence, evidence suggest that even in poor prognosis patients follicle, which in turn will suppress the early growth of the few ongoing pregnancy rates of around 20% can be achieved. other follicles residing in the ovary. This inhibitory effect on However, there are currently no results from prospective endogenous FSH—and early recruitment—can also be achieved randomized trials comparing DuoStim to two conventional in GnRH antagonist cycles, using short term daily estradiol stimulation cycles with cumulative live birth rate and time to live 4 mg, or oral contraceptives for 12–16 days as pre-treatment birth as end points. Importantly, in DuoStim a freeze-all policy without compromising reproductive outcome as compared to is mandatory, which includes additional manipulations with the long GnRHa down-regulation protocol (26, 27). As one biological material and costs for the patient or the health care more oocyte increases the live birth rate (LBR) by approximately system. Until further, we have to await the results of registered 5% (28, 29), a long GnRH agonist down-regulation protocol ongoing trials before final conclusions can be made. or a “primed” GnRH antagonist protocol as mentioned above should be considered first line treatment for the poor prognosis Choice of Gonadotropin patient. A recent retrospective study in POSEIDON groups 3 A Cochrane meta-analysis covering the normogonadotropic and 4 patients reported that a higher live birth rate per initiated IVF/ICSI population concluded that the type of gonadotropin cycle can be achieved in group 3 patients by using hMG in should be based on availability, convenience and costs (39). GnRHa down-regulation protocol as compared to hMG in GnRH Likewise, a large survey involving 314 centers from 73 countries antagonist protocol (7/54 = 13.0% vs. 78/283 = 27.6%, p = 0.024) worldwide concluded that the majority of respondents (62.2%) (7). This effect was not noted in POSEIDON group 4 patients. did not believe that there was a difference in efficacy between However, a retrospective analysis of 999 poor prognosis patients urinary (u) FSH and rFSH preparations and that the choice of (defined as AFC < 11 and AMH < 1.1 ng/ml) in the long down- gonadotropin was most often based on the individual preference regulation protocol and comparing a rLH + rFSH regimen to of the clinician (40). Despite no significant results comparing all hMG showed that rLH + rFSH was superior to hMG regarding types of uFSH with rFSH in normogonadotrophic women (28 the clinical pregnancy rate per started cycle (12.5 vs. 8.1%, P < trials, 7,339 couples, odds ratio (OR) 0.97, 95% CI 0.87–1.08) 0.02) (30). Interestingly, this effect was even more pronounced (39), a sub analysis observed that hMG was superior to rFSH in the patients with AFC<4 (10.2 vs. 1.5%, P < 0.01). Another as regards live birth rate per woman (11 trials, N = 3,197, OR protocol is the so-called mild stimulation protocol (31, 32), but 0.84, 95% CI 0.72–0.99). However, a recent meta-analysis of 70 this approach is poorly defined most often involving the GnRH prospective studies considering all gonadotropin combinations antagonist protocol using low dose gonadotropin stimulation and all ART outcomes, reported that recombinant FSH alone compared to a long GnRH agonist protocol with higher doses resulted in greater number of oocytes than hMG or rFSH+rLH of gonadotropin (33). Although recommended in the American (41). The addition of LH activity was useful to reduce the clinical guideline for POR (34), mild ovarian stimulation for amount of FSH needed and to improve pregnancy outcome, POSEIDON groups 3 and 4 is an approach not in line with but only if LH activity was provided by rLH rather than the POSEIDON stratification as discussed extensively in the hCG. In the context of this review, the question is whether paragraphs on natural cycle and FSH dosing. these results can be extrapolated to poor prognosis patients The recent advances in dual stimulation (“DuoStim”) and, admittedly, the results are difficult to interpret. When represents an interesting solution to accumulate embryos the effectiveness of the gonadotropin regimen is the focus of (blastocysts) within a short time span in order to obtain the the investigation, the primary endpoint should also include the number of blastocysts needed to increase the probability of ovarian response, which is a critical measurable parameter of having at least one euploid blastocyst for subsequent elective gonadotropin action (42). By contrast, pregnancy is the final frozen embryo transfer (eFET) (35–38). In a recent publication, result which is influenced by a multitude of factors, including Vaiarelli et al. (23) reported that poor prognosis patients endometrium receptivity, sperm factors, etc. In this regard, high (essentially POSEIDON group 4) undergoing a single “DuoStim” quality evidence overwhelmingly indicates that recombinant FSH cycle resulted in a total of 65.5% (203/310) of patients having is superior to urinary FSH and hMG as a means to increase at least one euploid blastocyst for transfer (23). Following the oocyte yield (43–47). Since the POSEIDON criteria relies on single euploid blastocyst transfer the ongoing pregnancy rate the individualized oocyte number to increase the likelihood of per transfer was similar comparing blastocysts obtained from having at least one euploid blastocyst for transfer, it seems sound Frontiers in Endocrinology | www.frontiersin.org 4 September 2019 | Volume 10 | Article 614 Haahr et al. Management of Poor Prognosis Patients to conclude that recombinant FSH, used alone or combined clinical value as compared to small and underpowered studies with recombinant LH, is the natural choice in Poseidon group which came to the conclusion that a higher oocyte number does 4 patients. The use of gonadotropin regimens combining recFSH not lead to a higher number of good quality embryos (57) As and LH activity supplementation by recLH in Poseidon group 4 regards the maximum daily FSH dose, it was shown that rFSH might offer additional clinical benefit, as discussed in the next dosing above 300 IU rFSH daily does not seem to increase the section, owing to a fine-tuned modulation of the PKA pathway LBR (58). In fact, a large retrospective study (N = 658,519) and proliferative/antiapoptotic signals, unlike hCG (42). In reported that daily dosing above 300 IU of FSH (including conclusion, hMG does not seem to add any clinically significant both uFSH and rFSH) significantly decreased the odds of a live benefit as regards reproductive outcomes in the GnRH antagonist birth (59). protocol, and likewise added LH activity in the long GnRHa down-regulation protocol seems to be better covered by r-LH ADJUVANTS TO OVARIAN STIMULATION than by hMG. Another agent for ovarian stimulation is Corifollitropin alfa Over the years many adjuvants to standard ovarian stimulation which has the pharmacokinetic advantage of a rapid increase have been proposed to increase LBR for the POR patient. In this in the FSH serum level which optimizes early recruitment paragraph we focus on relevant adjuvant therapy where evidence and increases the number of pre-ovulatory follicles (48). In a is relatively extensive; thus, excluding e.g., use of platelet enriched RCT including Bologna PORs only, there was no significant plasma, mitochondrial transfer and stem cells treatment where difference in live birth rate after fresh embryo transfer, evidence is based primarily on case series. however, significantly more embryos were cryopreserved in the group treated with Corifollitropin alfa followed by hMG Androgens as compared to a rFSH only regimen which hypothetically Pretreatment with androgens has been used for the POR patient would increase the cumulative live birth rate (49). From a in several trials. This approach could be considered for Poseidon POSEIDON point of view, it is important to achieve more groups 3 and 4 where, independently of age, the ovarian embryos in order to maximize the chance of having one euploid reserve is reduced and POR is expected. The main biological blastocyst for transfer, however, a larger sample size would evidence from the primate model is that androgens induce be needed to reach statistical significance as regards live birth FSH receptors on granulosa cells (60), which in turn increases rates (49). the recruitability and growth of pre-antral and antral follicles, through the IGF-1 system (61, 62). In 2012, two independent meta-analyses reported a significant positive effect of transdermal FSH Dosing: Individualization or One Size testosterone on the LBR of POR patients (63, 64). However, only Fits All? a total of 82 patients and 113 patients were included in the Recently, the OPTIMIST trial reported that a starting dose of intervention arm of the respective meta-analyses, which again 150 IU FSH (91% used rFSH) provided a similar cumulative included studies performed prior to the Bologna criteria. In LBR after 18 months follow-up as compared to individualized another meta-analysis of four RCT’s and 2 observational studies dosing with either 225 or 450 IU FSH in poor prognosis patients including a total of 528 patients, Zhang et al. (65) reported (N = 511), who were defined as having an antral follicle count that long-term DHEA treatment, the precursor of testosterone, of either 8–10 or <8, respectively (50, 51). Subsequently, the had a significant positive effect on the LBR of POR patients study was heavily criticized by many clinical researchers and as compared to controls (RR 1.87, 95% CI, 1.22–2.88) (65). for a multitude of reasons (52–54). First of all, the definition of Similarly, the latest Cochrane meta-analysis reported moderate poor prognosis was not in line with neither the ESHRE Bologna quality evidence supporting that DHEA and testosterone pre- nor the POSEIDON criteria (52). Secondly, the individualized treatment may improve LBR in POR patients (66). Although dosing significantly reduced cycle cancellation and increased the basic scientific and recent clinical evidence seems to support the number of good quality embryos for transfer and, finally, the use of androgen pre-treatment in POR, a recent commentary 18-month follow-up period for cumulative live birth rate was argued that the “androgen chapter” needs further study before criticized for not sufficiently covering supernumerary FET cycles recommendations can be made (67). Especially, the dosage and (54). In fact, to show an increase from 20 to 25% in LBR, more the timing of pre-treatment needs to be further elucidated; than 2,000 patients should have been randomized in order to hence an international clinical research group designed the achieve significant results (53). Hence, the conclusion of the so-called TTRANSPORT TRIAL for Bologna POR patients OPTIMIST trial suffered from many shortcomings and, in our (Clinicaltrial.gov identifier NCT02418572), evaluating androgen opinion, the current best practice in managing poor prognosis pre-treatment exceeding 60 days, and using a daily dose of patients should be to individualize the ovarian stimulation in 5.5 mg transdermal testosterone. This study designed to include order to increase the oocyte yield which is the only key to a large population of Bologna POR patients uses androgen pre- optimize LBR as seen in large cohort studies (29, 55, 56). In fact, treatment in a daily physiological dose and for an extended a pivotal study by Sunkara et al. (N = 400,135 cycles) found that time compared to previous trials, taking the time needed for increasing the oocyte yield from 2 to 3 resulted in a 25% relative folliculogenesis into account. The results of this trial -when increase in LBR across all age groups (29). Thus, results from completed- could help clarify the clinical utility of pre-treatment large databases with LBR as outcome have a significantly higher with androgens in poor prognosis patients. Frontiers in Endocrinology | www.frontiersin.org 5 September 2019 | Volume 10 | Article 614 Haahr et al. Management of Poor Prognosis Patients LH Supplementation a lower gonadotropin consumption (82–84). However, meta- The physiological rationale for LH supplementation is primarily analyses until now failed to show differences in LBR, perhaps as based on the “two cell two gonadotropin” concept (68, 69), a result of most trials being underpowered and using different in which LH supplementation stimulates the conversion of definitions for POR. Moreover, there is high interstudy variability cholesterol into androgens in the theca cell, thus, increasing regarding the route, timing and dose of GH administration. The endogenous intra-ovarian androgen production and follicular general pattern has been to explore GH adjuvant treatment using growth. On one hand, androgens (i) stimulate FSH receptor the same rationale as for androgen supplementation i.e., pre- expression on granulosa cells (60) (ii) act synergistically with treatment for some weeks before stimulation to hypothetically IGF1 for the growth of the follicle (62) and in animal models increase the number of recruitable follicles. In this line, a increase the number of pre-antral and antral follicles (70). On the recent double-blind, placebo-controlled randomized trial was other hand, LH binding to granulosa cell LH receptors–expressed performed in 10 centers throughout Australia and New Zealand from the mid-follicular phase onwards- sustains FSH dependent in POR patients, however, and importantly not aligned with the granulosa cell activities, including aromatase induction, release of Bologna or the POSEIDON criteria (85). After 4 years that study growth factors and regulates final follicle/oocyte maturation (71, was stopped after randomization of a total of 130 patients. Unlike 72). To study the possible clinical effect of rLH supplementation other studies, no statistical differences were reported between Lehert et al. (73) published a meta-analysis based on 6,443 cycles groups regarding the mean number of oocytes retrieved (5 vs. in normal and poor prognosis patients (non-Bologna criteria) 4, rate ratio 1.25, 95% CI 0.95–1.66) and the chance of reaching who were supplemented or not with rLH (73). Importantly, embryo transfer [53/61 [86.9%] vs. 42/51 [82.4%], OR 1.42, in that analysis it was not possible to distinguish between 95% CI 0.50–4.00]. However, results from this study should be hypo responder and POR patients. While rLH supplementation interpreted with caution as the study was pre maturely stopped improved clinical pregnancy rates by 9% (NS) in the overall and as such was underpowered. population, the effect was more pronounced in PORs with a relative risk (RR) of 1.30 (95% CI, 1.01–1.67). Recently, Coenzyme Q10 (CoQ10) Humaidan et al. (22) published the results of the largest RCT in CoQ10 pre-treatment for 60 days prior to ovarian stimulation poor prognosis patients aligned with the ESHRE Bologna criteria was very recently investigated in a RCT in POSEIDON group and POSEIDON group 4 criteria. In this trial, a total of 939 3 patients (N = 169 patients) (8). The hypothesis was that patients were randomized to either a fixed daily dose of either 300 CoQ10 would reduce mitochondrial oxidative stress and thus, IU rFSH plus 150 IU r-LH or rFSH 300 IU alone (22). The results improve oocyte competence. The study showed a significant indicated no significant differences between groups regarding difference in the CoQ10 supplemented group regarding number LBR. However, a post-hoc analysis, stratifying patients into mild, of oocytes retrieved [4 (mean), IQR 2–5] as compared to controls moderate or severe POR observed that the moderate and severe [2 (mean), IQR 1–2], p = 0.002, despite the fact that significantly PORs benefitted significantly from 150 IU rLH supplementation less FSH was consumed in the CoQ10 supplemented group. In in terms of a higher LBR and a lower total pregnancy loss (22). addition, the CoQ10 group had more high-quality day 3 embryos Finally, two more recent systematic reviews indicated that rLH defined as embryos that reached 6 to 8-cell stage with cytoplasmic supplementation is beneficial in women with hypo-response and fragmentation occupying <10% of the embryo surface and in women 36–39 years of age, reinforcing the idea of testing this had equal size blastomeres. The major limitation, however, approach in Poseidon group 4 (74, 75). was the lack of a placebo group. More studies are definitely needed in the area of pre-treatment with CoQ10, including Growth Hormone antioxidants in general and specifically for POSEIDON group 3 Growth Hormone (GH) has been explored therapeutically in and 4 patients. Importantly, CoQ10 and other antioxidants are ART for more than 30 years. The biological rationale for its use is promising adjuvants keeping in mind that they seem to cause no that GH itself has a synergistic effect to that of FSH on follicular or very limited adverse reactions and side effects (8). development and also through its downstream mediator, Insulin- like Growth Factor 1 (IGF-1), as seen in animal models (76, 77). OVULATION TRIGGER STRATEGY All models which block or impair the action of GH, result in a delay in puberty, a significant reduction on litter size and a In a recent review (86), the subject of individualized ovulation delay in the exhaustion of the follicular pool (78). Subsequent triggering (OT) was covered in detail. For the present review microscopic examination of the ovaries in these animal models we extract the important message that achieving the maximum shows an increase in primordial and primary follicles and a number of mature oocytes can be improved not only by the use decrease in the number of growing antral and pre-ovulatory of an individualized COS protocol, but also by individualizing follicles (78–80). Knock-out female mice failed to ovulate either the OT strategy. The key for success when using an OT agent spontaneously or under the influence of gonadotropins, proving is to reach an optimal LH activity level after trigger, resulting the importance of GH and IGF1 in increasing the sensitivity in the retrieval of more than 75% mature oocytes and without to gonadotropins during the whole process of selection and increasing the risk of OHSS development (87). A previous follicular growth to ovulation (81). Until now, scientific evidence cycle with a low follicle:oocyte ratio (FOI) could reflect lack suggests that adjuvant treatment with GH for POR patients of an appropriate follicular response to trigger which could be in IVF leads to a higher number of oocytes retrieved and associated to ovarian aging, poor ovarian reserve or even to Frontiers in Endocrinology | www.frontiersin.org 6 September 2019 | Volume 10 | Article 614 Haahr et al. Management of Poor Prognosis Patients FIGURE 3 | Best practice in POSEIDON groups 3 and 4. (A) Pre-treatment is rarely the first option in poor prognosis patients, but in case of unsuccessful ovarian stimulation, i.e., inadequate ovarian response, pre-treatment should be considered. The choice should rely on availability, clinical experience and patient preference. Stimulation protocol might start using GnRH antagonist co-treatment keeping in mind the possibility of converting to DuoStim to achieve the individualized oocyte number (according to the ART calculator). Otherwise a long GnRHa protocol should be considered first choice. (B) Ovarian stimulation strategy: First choice in Poseidon group 3 is the GnRH antagonist cycle with either 300 IU daily of rFSH alone or Corifollitropin alfa followed by either rFSH or hMG. In POSEIDON group 4 patients, rLH (75–150 IU daily) should be added from day one of stimulation unless the combination of Corifollitropin alfa and hMG was chosen. The GnRH antagonist cycle allows use of Duostim, unlike the long-agonist GnRH analog. (C) Ovulation trigger strategy: In the long GnRHa down-regulation protocol hCG is mandatory as ovulation trigger, whereas GnRHa is mandatory in the follicular phase stimulation of the DuoStim protocol. All trigger agents can be used in the luteal phase stimulation. In non-DuoStim GnRH antagonist cycles, the choice of trigger between GnRHa and hCG should rely on the embryo transfer strategy (fresh or frozen), patient characteristics (e.g., hypo-hypo) and clinical experience. In cases with a low FOI as determined on trigger day, clinicians should consider pre-treatment including short term estrogen therapy or OCP for synchronization of the follicles prior to stimulation, adjuvant LH activity during stimulation, or changing trigger strategy to either dual or double trigger. In case of an insufficient number of oocytes retrieved as determined by the ART calculator, the probability of transferring a euploid embryo should be discussed with the patient to counsel whether an immediate transfer or a new stimulation should be suggested. mutations of the LH receptor (5, 86, 88). However, a low FOI can stimulate the LH receptor due to molecular similarities (89); be largely improved by carefully considering the OT strategy. nevertheless hCG is characterized by having a longer half-life compared to LH (90) and this fact conditions the physiology of Human Chorionic Gonadotropin the corpora lutea and luteal phase hormonal profile. Using hCG Human chorionic gonadotropin (hCG) has been used as a as OT agent ensures an action at the level of the follicle regardless surrogate to LH for more than 30 years. Both gonadotropins of the pituitary status and hCG trigger with a standard luteal Frontiers in Endocrinology | www.frontiersin.org 7 September 2019 | Volume 10 | Article 614 Haahr et al. Management of Poor Prognosis Patients phase support has been shown to yield comparable reproductive the number of cycles included in these series was 1, 12, 8, and outcomes as compared to GnRHa trigger and a modified luteal 33, only. phase support policy (11). HOW TO TAILOR THE MOST OPTIMAL ART GnRHa GnRHa is a synthetic peptide that interacts with the GnRH TREATMENT ENCOMPASSING THE receptor releasing LH and to a lesser extent, FSH after activation. DIFFERENT TOOLS MENTIONED TO In a GnRH antagonist cotreated-cycle, a bolus of GnRHa ACHIEVE AT LEAST ONE EUPLOID displaces the GnRH antagonist from the receptor which induces BLASTOCYST FOR TRANSFER a flare of LH and FSH and subsequently, oocyte maturation and ovulation (91). The amount of LH (and FSH) secreted after Based on the abovementioned evidence, we developed an GnRHa trigger is significantly reduced in comparison with the expert opinion algorithm on how to manage POSEIDON natural cycle (92) which leads to implantation failure and early group 3 and 4 patients, see Figure 3. As explained earlier, the pregnancy loss after fresh embryo transfer, when using a standard suggestions for management is based on “very poor evidence” LPS, only (93). However, good quality oocytes and embryos in terms of GRADE (Grading of Recommendations Assessment, were obtained after GnRHa as well as after hCG triggering (94). Development and Evaluation). Thus, more research is needed Moreover, significantly more MII oocytes and embryos were and the suggested recommendations should preferably be used obtained after GnRHa trigger as compared to hCG trigger in a in future RCT‘s or at least clinicians should have retrospective recent retrospective analysis in cancer patients undergoing COS database capture of their results. Despite the poor evidence until and cryopreservation (95). This finding was supported by a recent now, we believe our suggestions represent current best practice. systematic review and meta-analysis, in which two RCTs showed a significant increase in the number of good quality embryos after GnRHa trigger as compared to hCG trigger, MD 0.94, 95% CI CONCLUSIONS 0.01, 1.87 (11). Poor prognosis patients challenge IVF clinicians every day. Herein, we extracted and discussed best practice for these Combination of OT Agents patients. Although more research is needed to make firm clinical OT strategies such as “dual trigger” and “double trigger” have recommendations, it is interesting that the treatment concepts been explored mainly in patients with a low FOI in a previous discussed herein resulted in ongoing pregnancy rates above 20% cycle or a low proportion of mature oocytes and these strategies per cycle (Duostim) for POSEIDON groups 3 and 4. Future trials have been suggested to improve IVF outcomes, to some extent investigating pre-treatment strategy, ovarian stimulation strategy overcoming impairment in follicular function, oocyte meiotic and ovulation trigger strategy are warranted and should be based maturation and cumulus expansion (86). Dual trigger is defined on a more detailed patient stratification such as suggested by the as the combined use of GnRHa and a low-dose of hCG, POSEIDON Group. administered simultaneously (96). In contrast, Double trigger is defined as the administration of GnRHa and hCG for OT at 40 and 34 h, respectively, prior to oocyte retrieval (97). Both AUTHOR CONTRIBUTIONS strategies combine the advantages of GnRHa and HCG: the direct The style and concept were developed by TH and PH. TH intrafollicular LH activity mediated by hCG, the simultaneous produced Figure 3 using visme.co with critical revisions from induction of an endogenous FSH surge mediated by GnRHa, and all authors. All authors contributed to writing the manuscript, the support of the early luteal phase LH activity mediated by hCG contributed with critical review and discussions regarding the (98). Double trigger adds the aspect of prolonging the interval final version of this review, and accepted the submission of this between OT and the oocyte retrieval which has been described manuscript for publication. as a strategy to increase the maturity rate of retrieved oocytes. The physiological rationale being that some patients may need a longer exposure time to the OT agent to allow cumulus expansion ACKNOWLEDGMENTS and detachment of the oocyte (99). However, the evidence for the use of double trigger in patients with low oocyte/follicle We acknowledge the authors of the cited studies who researched yield, low M-2 rate or poor responders is very limited, reported within the field of the in poor prognosis patients. Moreover, we by 2 groups, only, both from Israel (87, 97, 98, 100); thus, gratefully thank our colleagues at the respective IVF Centers who awaiting confirmation by further large scaled RCTs. Importantly, supported the research. 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The remaining author declares that the research was conducted in the absence of (2019) 38:908–15. doi: 10.1016/j.rbmo.2019.02.003 any commercial or financial relationships that could be construed as a potential 86. Dosouto C, Haahr T, Humaidan P. Advances in ovulation trigger strategies. conflict of interest. Panminerva Med. (2019) 61:42–51. doi: 10.23736/S0031-0808.18.03537-1 87. Zilberberg E, Haas J, Dar S, Kedem A, Machtinger R, Orvieto R. Co- Copyright © 2019 Haahr, Dosouto, Alviggi, Esteves and Humaidan. This is an open- administration of GnRH-agonist and hCG, for final oocyte maturation access article distributed under the terms of the Creative Commons Attribution (double trigger), in patients with low proportion of mature oocytes. Gynecol License (CC BY). The use, distribution or reproduction in other forums is permitted, Endocrinol. (2015) 31:145–7. doi: 10.3109/09513590.2014.978850 provided the original author(s) and the copyright owner(s) are credited and that the 88. Zreik TG, Garcia-Velasco JA, Vergara TM, Arici A, Olive D, Jones EE. original publication in this journal is cited, in accordance with accepted academic Empty follicle syndrome: evidence for recurrence. Hum Reprod. (2000) practice. No use, distribution or reproduction is permitted which does not comply 15:999–1002. doi: 10.1093/humrep/15.5.999 with these terms. Frontiers in Endocrinology | www.frontiersin.org 11 September 2019 | Volume 10 | Article 614