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Sec. Reproduction

Volume 15 - 2024 | https://doi.org/10.3389/fendo.2024.1231585

Subtle perturbations of ovarian steroidogenesis in patients classified as Poseidon Group 3. Which consequences for therapeutic strategy?

Jean Noel Hugues*Jean Noel Hugues

*

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University Sorbonne Paris Nord, Villetaneuse, France

The optimal strategy for stimulation of young women with a low ovarian reserve is still a challenging issue because the physio-pathogeny of this disorder is often unknown. As androgen production by the ovary plays a crucial role in folliculogenesis, it was tempting to speculate that subtle perturbations in ovarian steroidogenesis might participate to the low responsiveness to gonadotrophins. Indeed, in vitro analysis of human luteinized granulosa cells has recently provided evidence for some enzymatic deficits in steroidogenesis and altered response to gonadotrophins. Therefore, improving androgen environment of women classified in Poseidon Group 3 should be considered. In this clinical situation, the potential benefit of androgen supplementation or stimulation of theca cells by LH-activity products are respectively discussed.

Introduction

A new stratification of low responders to ovarian stimulation has been recently described based on the combination of both qualitative (age) and quantitative parameters (serum AMH, Antral Follicular Count) allowing to identify 4 different groups ( 1). A hypo-response is usually associated with a poor prognosis of fertility when ovarian parameters are altered (AFC < 5 - AMH < 1.2 ng/ml), even in young (< 35 yrs) women (Poseidon Group 3). As physio-pathogeny of ovarian hypo-response is still often unknown and likely related to various mechanisms, strategies usually suggested such as prescription of higher FSH doses and/or addition of products with LH-activity proved to be partly ineffective to improve follicular recruitment and/or the number of good quality embryos.

It was well demonstrated that follicular development is dependent on several ovarian paracrine factors with a special focus on the critical role of androgens on ovarian physiology. The purpose of this article is to gain an insight into the consequences of an altered steroidogenesis on the ovarian response to stimulation and to discuss the optimal way to counteract this defect.

Androgens and folliculogenesis

While androgens have traditionally been considered detrimental to ovarian function, the development of different types of androgen receptor (AR) knock out models along with various in vivo and invitro studies allowed to establish that androgen action through specific receptors is required to get normal ovarian development. In many species, AR are expressed in different ovarian compartments but are most abundant in the pre-antral/antral stages of follicular development while they decline as follicle matures to the pre-ovulatory stage ( 2). In primates, Weil et al. demonstrated that testosterone, in a positive feedback loop, increases AR expression in theca and granulosa cells of pre-antral follicles ( 3).

In 1981, Hillier et al. provided evidence that granulosa cell aromatase induction/activation by hFSH is an androgen receptor-regulated process ( 4). Regarding follicular development, several studies demonstrated that androgen treatment enhances pre-antral follicular growth and improves ovarian response by increasing granulosa cell proliferation (Ki67) and by attenuating follicular atresia ( 5). Furthermore, administration of androgens in monkeys initiates follicular recruitment, stimulation of early stages of follicular growth and increase in the number of growing follicles ( 6). While these observed effects could be blocked by anti-androgens ( 7), it is still uncertain whether they are the consequence of direct androgen actions or due to the conversion of androgens to oestrogens.

What about androgen signalling in the ovary? The classic mode of androgen action, as for most steroids, involves binding of androgen to AR in the cell cytoplasm and translocation of the hormone-receptor complex to the nucleus where it binds to a specific sequence in the promotor of the relevant target gene and promotes gene transcription. According to this model, androgens induce follicle-stimulating hormone receptor (FSHR) mRNA expression during pre-antral to antral follicle progression in different species including primates ( 6, 8). More recently, in human granulosa cells, a positive correlation has been found between mRNA levels of AR/FSHR and androgen levels in follicular fluid ( 9). Altogether, these data indicate that androgen stimulation enhances follicular sensitivity by increasing FSHR levels, which contributes to follicle growth. In addition, the study by Sen et al. ( 10) indicated that androgens increase FSHR protein levels in a nongenomic transcription-independent fashion. Indeed, androgens, through PXN-regulated genomic (Paxillin implicated in translocation of AR to the nucleus) as well as non-genomic AR actions, induce the expression of a micro-RNA ( miR-125b) that decreases pro- apoptotic proteins, thereby contributing to androgen-induced follicular survival.

Additionally, in isolated mouse preantral follicles, incubation with DHT greatly enhances expression of the steroid acute regulatory protein (StAR, a key regulator of steroidogenesis) in response to FSH ( 11). In the same model, both testosterone and DHT interact with members of the TGFβ superfamily, reducing gene expression of anti-Mullerian hormone (AMH) (produced by granulosa cells) and of bone morphogenetic protein- 15 (BMP-15) (produced by the oocyte) which may have inhibitory effects on follicle growth ( 11). As shown in Figure 1, the combined effects of DHT, positive on FSHR expression and negative on the growth- inhibitory AMH and BMP-15, indicate that the regulation of pre-antral follicular growth is dependent on a complex balance between endocrine and local growth factor actions ( 12).

Figure 1 Proposed pathways of androgen action on preantral follicle growth ( 12). Testosterone or/and DHT act via the androgen receptor, increasing granulosa cell proliferation. This may be mediated directly, or indirectly by increased FSHR (stimulating GC proliferation) or decreased AMH (reducing AMH inhibition). AMH can be further reduced by androgen-induced reduction of oocyte-specific BMP15, which normally stimulates AMH levels.

Finally, Testosterone and DHT raise the transcript levels of insulin-like-growth 1 (IGF-1) and IGF1 receptors in primate ovaries ( 13). The presence of IGF- 1 and IGF-1 receptor mRNA in granulosa cells, theca, oocytes and interstitial cells and the fact that IGF-1 suppresses follicular apoptosis suggests that androgens may have a direct impact on improving the quality of oocytes and produced embryos ( 14).

Altogether these data clearly demonstrate the crucial role of androgens in the regulation of folliculogenesis. Therefore, we may speculate that any defect in androgen production could actually be associated with a hypo-response to stimulation. Consequently, a deep assessment of ovarian androgen biosynthesis could be valuable in patients with a poor ovarian response to FSH stimulation.

Regulation of ovarian steroidogenesis

Steroid biosynthesis requires complex interactions that have been extensively studied. Cholesterol is the unique precursor derived from circulating LDL lipoproteins which are internalized by receptor-mediated endocytosis. LDL proteins are then degraded by proteolysis with liberation of cholesterol esters, subsequently hydrolyzed to free cholesterol by lysosomal acid lipase (LAL) ( Figure 2) ( 15).

Figure 2 Intracellular cholesterol trafficking ( 8).

Then, the entry of cholesterol into steroidogenic mitochondria is dependent on action of StAR (Steroidogenic Acute Regulatory protein) which triggers the acute steroidogenic response. As shown in Figure 2, StAR acts on the outer mitochondrial membrane (OMM) and triggers cholesterol flux to inner mitochondrial membrane (IMM) where it can be converted to pregnenolone by 450scc to initiate steroidogenesis.

Most enzymes involved in steroid biosynthesis are either cytochrome P450s (CYPs) or Hydroxysteroid Dehydrogenases (HSDs). The human genome includes genes for 57 CYPs, 7 being targeted to the mitochondria (Type 1), the other 50 (Type 2) to the Endoplasmic Reticulum (ER). Six P450 enzymes participate in adrenal/ovarian steroidogenesis.

Classically, a cell is called "steroidogenic" if it expresses the cholesterol side-chain cleavage enzyme, P450scc, which catalyses the first step in steroidogenesis. The conversion of Cholesterol to Pregnenolone in mitochondria is the first rate-limiting and hormonally regulated step in the synthesis of all steroid hormones. Therefore, P450scc is a key factor because it determines net steroidogenic capacity, so it serves as the chronic regulator of steroidogenesis. Ovarian expression of P450scc induced by LH-mediated cAMP, cleaves the 20,22 bond of insoluble cholesterol to produce soluble pregnenolone ( Figure 3). Then, Pregnenolone may be metabolized into 2 distinct directions.

⚬ Pregnenolone may exit the mitochondria to become the substrate for P450c17 in the ER which catalyses both 17-hydroxylase and 17,20 lyase activities and produce 17OH-Pregnenolone and DHEA (Δ5 pathway).

⚬ Alternatively, Pregnenolone may be converted to Progesterone by 3ß-hydroxysteroid dehydrogenase (3ßHSD) present in mitochondria. This enzyme similarly controls, in the ER, the conversion of hormones from Δ5 pathway to Δ4 pathway: 17α-hydroxy-pregnenolone to 17α-hydroxyprogesterone (17OHP), DHEA to Androstenedione and Androstenediol to Testosterone.

⚬ In addition, P450c17 acts to convert Progesterone to 17OH- Progesterone and Androstenedione.

⚬ The final step leading to the production of Testosterone is controlled by 17ß Hydroxysteroid dehydrogenase (17ß HSD2).

Figure 3 Schematic representation of enzymatic control of ovarian steroidogenesis.

Another key point in ovarian steroidogenesis is that granulosa cells do not express P450c17. Thus, in general, steroidogenesis is initiated in granulosa cells under the influence of LH which stimulates the expression of P450scc. Pregnenolone and Progesterone from granulosa cells diffuse into adjacent theca cells where they can be acted upon by P450c17 and 3ßHSD to produce Androstenedione which is partly converted to testosterone by 17ß HSD2. Finally, testosterone leaves the theca cell compartment to granulosa cells where it is converted to Oestradiol by aromatase (CYP) stimulated by FSH.

These data attest for a critical role of both cholesterol metabolism inside mitochondria to initiate steroidogenesis and steroidogenic enzymes of ovarian compartments to produce oestradiol and progesterone on one side (granulosa cells) and androgens on the other side (theca cells).

Relationship between ovarian sensitivity to FSH and steroidogenesis

This very close relationship between androgen production and folliculogenesis was the rationale of the study conducted by Prof Okten's team in Turkey ( 16). The main objective here was to perform an extended analysis of the steroidogenic capacity of human luteinized granulosa cells obtained in young patients who experimented hypo-response to ovarian stimulation related to poor ovarian reserve. For that purpose, 40 young (35 yrs) women programmed in an IVF program following stimulation by r.hFSH with GnRH antagonist were included in this study. Twenty of them were control patients who had documented a normal response to ovarian stimulation (8-15 retrieved oocytes) whereas the remaining 20 were classified as poor responders because of the collection of 3 oocytes in the current IVF cycle and a diminished ovarian reserve (DOR: AFC < 5 and AMH < 1.1 ng/ml).

The luteinized granulosa cells were obtained from follicular aspirates during the oocyte retrieval procedure and cultured individually. Their analysis allowed to get the following results:

● mRNA expressions of steroidogenic components (StAR-3ßHSD-aromatase) and of gonadotropin (FSH-LH) receptors measured by qRT-PCR were significantly decreased in poor responders as compared to control group. These data were confirmed by immunoblot analysis who showed that expression of StAR, 3ßHSD and aromatase was decreased in granulosa cells of poor responders.

● Basal steroidogenic capacity of granulosa cells, assessed by in vitro E2 and P production, was significantly reduced in poor responders. Furthermore, in accordance with a defective expression of gonadotropin receptors, granulosa cell response to FSH (upregulation of StAR and E2 production) and to hCG (increased expression of StAR and P production) were significantly lower in poor responders as compared to control group. The data attest for a significant deficit in basal/stimulated steroidogenesis in poor responders.

● The conventional immunofluorescence microscopy examination displayed a reduced cytoplasmic accumulation of intracellular lipids in the cells of poor responders. A more detailed analysis by confocal microscopy showed that the lipid content inside mitochondria was significantly decreased. Additionally, the confocal images analysis indicated that the signal intensities of StAR and 3ßHSD were significantly reduced and their colocalizations with mitochondria were markedly reduced.

● Finally, a substantial delay and reduction in cholesterol uptake, cytoplasmic accumulation and transportation to mitochondria were observed in poor responders. This reduced cholesterol trafficking was related to a decreased expression of LDL receptors.

Taken together, these findings, translated into clinical practice, indicate that POR to stimulation in young individuals with DOR should not simply be considered as a state of lesser follicle growth or oocyte yield. Rather, the underlying molecular perturbations of POR are much more complex and involve multiple steps of steroidogenesis (HDL receptors, cholesterol trafficking, expression of steroidogenic enzymes) and gonadotropin responsiveness.

To date, a limited number of studies have analysed the steroidogenic characteristics of luteinized GCs obtained from a heterogenous population of patients with DOR, advanced age, and POR. The existing data are somewhat inconsistent mainly because of methodologic or technical limitations ( 17, 18). In accordance with Turkish data, Phy et al. ( 19) demonstrated lower StAR expression and P4 production in the luteinized GCs of patients with DOR. In addition, it was previously reported that granulosa cells of elderly women (38-41 years) display defective mitochondria and fewer lipid droplets than the cells of a younger group ( 20, 21) and a reduced mitochondrial DNA content ( 22). Therefore, it might be speculated that ovarian hypo-response to stimulation of young women reflects an ovarian premature senescence. Although there is still no consensus on the exact definition of premature senescence, recent studies using whole-genome methylation array reported that luteinized granulosa cells of advanced-age women with DOR have a distinct epigenic profile and harbour a high frequency of epimutations suggestive of premature aging ( 23, 24).

Another issue to be addressed is whether the analysis of luteinized granulosa cells actually reflects the quality of ovarian steroidogenesis in absence of stimulation. In these young poor responders, theca cell function was not specifically assessed but, presumably, androgen (androstenedione, testosterone) biosynthesis is going to be reduced due to defective cholesterol trafficking inside mitochondria and low steroidogenic enzyme expression as well.

The close relationship between androgen production and folliculogenesis allows to assume that a hypo-androgen situation might participate in the event of ovarian hypo-response. Previous publications reported a significant decrease in androgen production in elderly women ( 25), a hypo-response to hCG ( 26) and a close correlation between basal androgen levels and the number of collected oocytes in normo-responders ( 27). These data are consistent with previous report ( 28) that, in young poor responders referred as group 3 in Poseidon classification, serum testosterone and androstenedione values were significantly lower than in the control group and in the Poseidon group 1. Nevertheless, as serum and follicular fluid testosterone concentrations are not positively correlated ( 29), androgen concentrations within follicular fluids were not significantly different ( 30).

Therapeutic strategies in women classified as Poseidon Group 3

Altogether, these data indicate that the degree of androgen production is likely to be predictive of the granulosa response to FSH. Therefore, what benefit could be expected from improvement of androgen environment in poor responders? Furthermore, as androgens interfer from the early stages of folliculogenesis, any addition of drugs should be prescribed prior to the ovarian stimulation itself. Such a "priming effect" can be achieved throughout two different approaches:

*either a "systemic androgen priming" via supplementation with androgen (usually gel application) to increase circulating androgen levels.

*or an "intra-ovarian androgen priming" via administration of LH-like products and/or aromatase inhibitors to increase local androgen production both being performed during the period preceding the ovarian stimulation.

Androgen supplementation

The first prospective, randomized clinical trial ( 31) indicated that a pre-treatment with daily application of testosterone gel (10 mg/day) during 15 days was associated with a significant increase in serum Testosterone values (from 0.58 ± 0.16 to 1.55 ± 0.89 ng/ml (P < 0.0001) but the improvement in ovarian parameters following this protocol was limited to a modest increase in the number of mature oocytes. Nevertheless, in accordance with other reports ( 32- 35), a recent meta-analysis ( 36) of 8 randomized clinical trials (797 women) showed that a daily application of Testogel (10 to 12.5 mg/d) during 10 to 56 days before ovarian stimulation can significantly improve ovarian response to FSH stimulation:

* Increase in the number of cumulus-oocyte complex (WMD 0.88, 95% CI 0.22-1.54).

* Decrease in the duration of treatment & requirement of lower gonadotrophin doses (WMD - 368.8 IU, 95% CI - 612.4 to -125,3 IU).

* Higher clinical pregnancy and birth rates (RR 2.25, 95% CI 1.54-3.30 and RR 2.07, 95% CI 1.09-3.92 respectively).

Conversely, no differences were observed regarding the numbers of follicles ≥ 17mm, metaphase II oocytes, two-pronuclear oocytes and embryos transferred.

In addition, some limitations were underlined by the authors: a large variability in the definition of poor ovarian response (< 4 oocytes retrieved in previous stimulations despite high doses of gonadotrophins - Bologna criteria - Poseidon criteria), some concerns regarding the randomization process (only 3 studies at low risk) and, finally, a high heterogeneity regarding the duration of testosterone pre-treatment. Interestingly, the largest randomized clinical trial which compared 4 and 6 weeks of testosterone application could not find any difference between the 2 groups regarding the number of collected oocytes or IVF out-come ( 37). This conclusion was confirmed in another prospective study comparing the effects of 10 to 56 days of androgen gel application to a small number of poor responders ( 38). Even if a short supplementation may offer the advantages of lower cost, patient-friendly prescription and reduction in the risk of therapy interruption, these data do not support the concept that a long-term effect of androgens is required to improve folliculogenesis. Unfortunately, no data actually exist regarding the consequences of short or long-term systemic testosterone administration on intra-follicular androgen levels.

No side effects were reported whatever the duration of gel application. However, the long- term effects of testosterone pretreatment have not been currently studied. Similarly, no data are available on children born after testosterone pretreatment.

Altogether, these data indicate that systemic androgen supplementation is likely to be beneficial not only on stimulation parameters but, most importantly, in terms of live birth rate. Nevertheless, additional prospective randomized studies are needed in a large number of poor responders even if everybody knows that this population is rather reluctant to be included in randomized trial. In addition, relevant RCTs should allow to determine the optimal duration of supplementation in a well-defined population of poor responders. This therapeutic approach may offer new interesting perspectives in young women whose prognosis of fertility is likely to be fair because the embryonic aneuploidy rate is still low ( 39).

Stimulation of androgen production (LH-hCG-aromatase inhibitors)

As Luteinizing Hormone (LH) plays a crucial role in folliculogenesis, several studies assessed the efficacy of LH supplementation in IVF protocols using GnRH agonists/antagonists in patients with normal ovarian function and some beneficial effects of LH addition were observed in elderly (> 35yrs old) women ( 40) and hypo-responders (4-9 oocytes) ( 41). In contrast, meta-analyses focused on women with poor response to FSH reported discordant conclusions ( 42, 43). In the specific group of young women with a poor response to FSH according to Poseidon classification, no clear advantage of adding LH to FSH could be demonstrated in Group 3 ( 44) as well as in Group 4 ( 45).

However, in these studies, FSH and LH were concomitantly administered during the stimulation period. Therefore, the potential benefit of an "intra-ovarian androgen priming" was not assessed except in few situations:

* In women with hypo gonadotrophic hypogonadism, a 7-day priming with 300 IU of LH allowed to reduce the FSH threshold ( 46).

* Another study performed in normo-responders included in GnRHa stimulation protocol showed that a 7-day administration of 300 IU/d LH during the period of hypophyseal desensitization was associated with a modest clinical benefit ( 47).

* Finally, a randomized clinical trial performed in < 38yrs old women with previous poor response to FSH (n=43) showed that a pre-treatment of 4 days with 150 IU LH was associated with a modest increase in the number of oocyte and live birth rate ( 48).

However, to the best of our knowledge, no randomized clinical trial has been yet planned to assess the interest of LH priming in young poor responders classified in Poseidon Group 3. Meanwhile, the recent work by Casarini's team using human luteinized granulosa cells from normo (> 10 oocytes), hypo (4-9 oocytes) and poor responders (< 3 oocytes) ( 49) aimed to study the effects of in vitro LH addition on the FSH dose-response curves for cAMP and Progesterone production. Interestingly, this study showed that the efficacy of FSH is lower in hypo and poor than in normo-responders but addition of picomolar concentrations of LH increased the efficacy of FSH, bringing their response pattern like that of normo-responder cells treated with FSH alone.

Therefore, it is still uncertain whether LH supplementation of poor responders (Poseidon Group 3) could be effective to improve the ovarian response to FSH. As previously reported ( 50), the use of GnRH agonist test (GAST) with measurement of serum 17 OH Progesterone, a more sensitive index than Testosterone, could allow to identify patients who might benefit from addition of LH. Hopefully, these data could stimulate clinicians to launch new randomized prospective studies on that issue, even if the limitation of protocols with LH supplementation will be the cost effectiveness.

An alternative way to stimulate androgen production could be the use of hCG, another product with LH activity. Nevertheless, it should be emphasized that, while interacting with the same receptor, biological activity of LH and hCG are quite distinct. Indeed, recombinant LH exerts both proliferative and antiapoptotic actions through phosphorylated extracellular-regulated kinase 1/2 (pERK1/2) and phosphorylated AKT signals. By contrast, LH activity provided by hCG displays a steroidogenic and proapoptotic effect mediated by cAMP and protein kinase A (PKA) ( 51). Therefore, the specific effect of hCG priming needs to be specifically evaluated.

A limited number of studies assessing the effects of hCG prior to FSH administration has been performed up to now and a great majority associated the administration of aromatase inhibitors to block the conversion of androgen to oestrogen. Two preliminary studies were performed in women with normal ovarian function in order to assess the benefits of a "short-term androgen priming" using aromatase inhibitor and hCG administered during a early follicular phase down regulated by GnRH antagonist. The first one ( 52) tested the effects of a 7 day-period administration of aromatase inhibitor (Letrozole 2.5 mg/d) ± hCG (2.500 IU twice a week). A significant increase in follicular fluid levels of testosterone was observed in women receiving aromatase inhibitors, in accordance with previous reports ( 53) but most of the characteristics of ovarian stimulation and cycle outcome were unchanged. The second study published by the same Danish team ( 54) was prospective, randomized with a period of androgen priming limited to 3 days. Serum testosterone levels were slightly higher in the treated group but no significant increase in top quality embryos could be observed. These studies performed in women with normal ovarian function validated the concept of "short-term intra-ovarian androgen priming" using aromatase inhibitors and hCG to improve the androgen environment. Until now, very few studies have been performed in patients classified as poor responders according to Bologna criteria. The study by Bercaire et al. ( 55) assessed the effects of a combination of 3 drugs applied simultaneously during the cycle (28 days) preceding the FSH stimulation to poor responders: Transdermal testosterone 25 mg every other day, Letrozole 2,5 mg/d and hCG 2.500 IU twice a week. Unfortunately, this protocol was performed in a small number of < 40 yrs old women, preventing any firm conclusion. Further to previous observations from women with normal ovarian function, a "long-term intra-ovarian androgen priming" was proposed in order to boost the recruitment of small pre-antral follicles ( 56). For that purpose, during 2 months of hypophyseal desensitization induced by GnRH agonist (Depot formulation 3,75 mg every 4 weeks), a small dose of recombinant HCG (260 IU every second day) was administered subcutaneously in addition to oral letrozole 2.5 mg daily for 8 weeks. The results of this study were rather disappointing because the mean serum AMH levels decreased over time and no significant effects on Antral Follicular Count (AFC) could be observed. In addition, serum testosterone remained unchanged. Several reasons could explain the lack of benefit of this regimen: a too severe and prolonged pituitary down-regulation, an insufficient dose of hCG delivered every 2 days, a small number of patients ( 30), the single ethnicity population included. Consequently, another study was set up including women with low serum AMH who underwent 2 consecutive identical stimulation cycles separated by 8 weeks (2 cycles) of daily injection of 260 IU hCG ( 57). The primary end point was the assessment of FORT defined as the number of preovulatory follicles (>16mm) on hCG trigger day divided by the number of antral follicles (2-10 mm) at baseline who was similar in the 2 stimulation cycles. Surprisingly, circulating serum androgen levels were not increased at the end of the hCG priming period and testosterone levels within the follicular fluid of >17mm aspirated follicles were decreased at the end of the second cycle. Therefore, to validate the interest of a long-term hCG priming, the authors suggested to design a new study with the collection of follicular fluid from antral follicles before and immediately after priming in order to measure androgen levels and Androgen receptor and FSH receptor expression in small follicles ( 58). Additionally, these negative results should be interpreted in light of the data reported by Okten's team ( 16). Indeed, the significant deficit in basal / stimulated ovarian steroidogenesis reported in young poor responders could definitely explained the absence of positive effect of hCG administration. If we translate these data in clinical practice, this might indicate that no significant improvement in ovarian response can be expected when hCG in combination with Aromatase Inhibitors are prescribed in Poseidon 3 poor responders.

Conclusion

The actual involvement of androgens in the state of poor ovarian response to stimulation is highly suggested by several studies. However, additional research is needed in this area before clear recommendations about the value of systemic or intra-ovarian androgen priming in a clinical setting can be made. The recent study analysing the steroidogenic capacity of granulosa cells attests for a significant deficit in basal / stimulated steroidogenesis in poor responders. If these results are confirmed, they would lead to recommend a systemic rather than an intra-ovarian androgen priming. In addition, it is our feeling that a special focus should be made on young women with reduced ovarian function (Group 3 of Poseidon classification) because euploidy rate in their oocyte and embryos seems to be still preserved ( 39).

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References

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Frontiers | Subtle perturbations of ovarian steroidogenesis in patients classified as Poseidon Group 3. Which consequences for therapeutic strategy?

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The optimal strategy for stimulation of young women with a low ovarian reserve is still a challenging issue because the physio-pathogeny of this disorder ...

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Significance of serum AMH and antral follicle count discrepancy for the prediction of ovarian stimulation response in Poseidon criteria patients

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Significance of serum AMH and antral follicle count discrepancy for the prediction of ovarian stimulation response in Poseidon criteria patients

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Assisted Reproduction Technologies

Published: 15 February 2024

(2024)

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Journal of Assisted Reproduction and Genetics

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Alyssa Hochberg, Michael H. Dahan, Hakan Yarali, Lan N. Vuong & Sandro C. Esteves

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Abstract

Purpose

To determine the risk of not being a poor responder in ovarian stimulation (OS) for in vitro fertilization (IVF) when ovarian reserve markers are discordant-one falling within Poseidon's criteria normal range (e.g., anti-Müllerian hormone (AMH) ≥ 1.2 ng/mL or antral follicle count (AFC) ≥ 5), and the other in the poor ovarian reserve range.

Methods

A tri-center retrospective cohort study (2015-2017) involving women with discordant AMH and AFC values undergoing their first IVF/ICSI cycle using conventional OS (cOS, ≥ 150 IU/day of follicle-stimulating hormone). Discordant serum AMH and AFC values were defined according to Poseidon's criteria (AMH < 1.2 ng/mL and AFC ≥ 5 or AMH ≥ 1.2 ng/mL and AFC < 5). Poor ovarian response (POR) was < 4 retrieved oocytes. Receiver operating characteristic (ROC) curves were used to determine AMH and AFC cut-offs for non-POR. Logistic regression analysis evaluated factors associated with non-POR.

Results

Out of 8797 patients who underwent assessment with both AMH and AFC, 1172 (13.3%) exhibited discordant values. Of these, 854 (72.9%) had ≥ 4 oocytes retrieved. Within this group, 726 (85.0%) had "low" AMH values, whereas 128 (15.0%) had "low" AFCs. An AFC of 6 had 77% sensitivity and 52% specificity (AUC = 0.700), while AMH of 1.19 ng/mL had 31% sensitivity and 85% specificity (AUC = 0.492) for non-POR. AFC and the use of recombinant gonadotropins were positive predictors of non-POR.

Conclusions

When serum AMH is < 1.19 ng/mL, but AFC is ≥ 6, there is a moderate likelihood of a non-POR during stimulation. Conversely, if AFC is < 5 but serum AMH is ≥ 1.19 ng/mL, the chances of non-POR are low. Among patients with discordant markers, AFC emerges as the primary predictor of oocyte yield.

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Data availability

All data supporting the findings of this study are available within the paper.

References

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Authors and Affiliations

Department of Obstetrics and Gynecology, McGill University, 845 Rue Sherbrooke, O, Montreal, QC, 3HA 0G4, Canada

Alyssa Hochberg & Michael H. Dahan

The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Alyssa Hochberg

Anatolia IVF, Ankara, Turkey

Hakan Yarali

Department of Obstetrics and Gynecology, Hacettepe University, Ankara, Turkey

Hakan Yarali

Department of Obstetrics and Gynecology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam

Lan N. Vuong

IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam

Lan N. Vuong

HOPE Research Center, My Duc Hospital, Ho Chi Minh City, Vietnam

Lan N. Vuong

ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil

Sandro C. Esteves

Contributions

AH, MHD, and SCE designed the study and helped with data acquisition, analysis, and interpretation. HY and LV participated in data acquisition, interpretation, and article revision for critical intellectual content. All authors contributed intellectually to the writing or revision of the manuscript, approved the final version, and are accountable for all aspects of the work.

Corresponding author

Correspondence to Alyssa Hochberg.

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Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. The study received ethical approval from the institutions' ethics committees: Instituto Investiga, Brazil (CAAE 26429219.0.0000.5599); Hacettepe University, Turkey (KA-180070); and My Duc Hospital, Vietnam (05/18/DD-BVMD).

Informed consent

Informed consent was waived due to the retrospective design of the study.

Competing interests

MHD received unrestricted research grants from Merck Serono and Ferring. HY declares receipt of payment for lectures from Merck and Ferring. LNV receives speaker fees and conferences from Merck, Merck Sharp and Dohme (MSD), and Ferring and research grants from MSD and Ferring. SCE declares receipt of unrestricted research grants from Merck and lecture fees from Merck and MedEA. AH has no conflict of interest to declare.

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Hochberg, A., Dahan, M.H., Yarali, H. et al. Significance of serum AMH and antral follicle count discrepancy for the prediction of ovarian stimulation response in Poseidon criteria patients. J Assist Reprod Genet (2024). https://doi.org/10.1007/s10815-024-03050-8
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Keywords

# data[].attributes.attachment_link.title
Significance of serum AMH and antral follicle count discrepancy for the prediction of ovarian stimulation response in Poseidon criteria patients - Journal of Assisted Reproduction and Genetics

# data[].attributes.attachment_link.description
Purpose To determine the risk of not being a poor responder in ovarian stimulation (OS) for in vitro fertilization (IVF) when ovarian reserve markers are discordant-one falling within Poseidon's criteria normal range (e.g., anti-Müllerian hormone (AMH) ≥ 1.2 ng/mL or antral follicle count (AFC) ≥ 5), and the other in the poor ovarian reserve range.

# data[].attributes.attachment_caption
Eran Horowitz
Yossi Mizrachi 1
Elad Barber
Arieh Raziel
Sandro C. Esteves 2
Ariel Weissman 3
Show all authors
Show footnotes
Published:January 23, 2024DOI:https://doi.org/10.1016/j.ejogrb.2024.01.025

# data[].attributes.headline
High prevalence of low prognosis by the POSEIDON criteria in women undergoing planned oocyte cryopreservation

# data[].attributes.subject
High prevalence of low prognosis by the POSEIDON criteria in women undergoing planned oocyte cryopreservation

# data[].attributes.body
POSEIDON’s Stratification of "Low Prognosis Patients in ART": The WHY, the WHAT, and the HOW

# data[].attributes.attachment_link.description
Management of patients with an impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation has challenged reproductive specialists for a long time. Apart from our limited understanding of its pathophysiology, there is wide heterogeneity in the definition of POR and…

# data[].attributes.attachment_link.keywords[]
reproductive health services / organization & administration*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
COVID-19 and assisted reproductive technology services: repercussions for patients and proposal for individualized clinical management - PubMed

# data[].attributes.attachment_link.description
The prolonged lockdown of health services providing high-complexity fertility treatments -as currently recommended by many reproductive medicine entities- is detrimental for society as a whole, and infertility patients in particular. Globally, approximately 0.3% of all infants born every year are co ...

# data[].attributes.attachment_link.readable_text
doi: 10.3389/fendo.2019.00814.

Affiliations

1 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

2 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

3 Fertility Clinic Skive, Skive Regional Hospital, Skive, Denmark.

4 Faculty of Health, Aarhus University, Aarhus, Denmark.

5 Fertility Center Hamburg, Hamburg, Germany.

6 Laboratory of Reproductive Biology, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Copenhagen, Denmark.

7 Center for Gynecology, Endocrinology, and Reproductive Medicine, Ulm, Germany.

8 Department of Gynaecology, Jena-University Hospital-Friedrich, Schiller University, Jena, Germany.

9 Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.

10 Dexeus University Hospital, Barcelona, Spain.

11 Instituto Valenciano de Infertilidad, Rome, Italy.

12 Service de Médecine de la Reproduction et Préservation de la Fertilité, Hôpital Antoine Béclère, Clamart, France.

13 Anatolia IVF, Ankara, Turkey.

14 ORIGEN, Center for Reproductive Medicine, Rio de Janeiro, Brazil.

15 Department of Obstetrics and Gynecology, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam.

16 IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam.

17 Nova IVI Fertility, Ahmedabad, India.

18 GENERA, Center for Reproductive Medicine, Rome, Italy.

Free PMC article

Free PMC article

doi: 10.3389/fendo.2019.00814.

Affiliations

1 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

2 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

3 Fertility Clinic Skive, Skive Regional Hospital, Skive, Denmark.

4 Faculty of Health, Aarhus University, Aarhus, Denmark.

5 Fertility Center Hamburg, Hamburg, Germany.

6 Laboratory of Reproductive Biology, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Copenhagen, Denmark.

7 Center for Gynecology, Endocrinology, and Reproductive Medicine, Ulm, Germany.

8 Department of Gynaecology, Jena-University Hospital-Friedrich, Schiller University, Jena, Germany.

9 Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.

10 Dexeus University Hospital, Barcelona, Spain.

11 Instituto Valenciano de Infertilidad, Rome, Italy.

12 Service de Médecine de la Reproduction et Préservation de la Fertilité, Hôpital Antoine Béclère, Clamart, France.

13 Anatolia IVF, Ankara, Turkey.

14 ORIGEN, Center for Reproductive Medicine, Rio de Janeiro, Brazil.

15 Department of Obstetrics and Gynecology, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam.

16 IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam.

17 Nova IVI Fertility, Ahmedabad, India.

18 GENERA, Center for Reproductive Medicine, Rome, Italy.

Abstract

This article represents a viewpoint on the POSEIDON criteria by a group of clinicians and embryologists. Its primary objective is to contextualize the Poseidon criteria and their metric of success for the relevant Frontiers Research Topic "POSEIDON's Stratification of Low Prognosis Patients in ART: The WHY, the WHAT, and the HOW". "Low prognosis" relates with reduced oocyte number, which can be associated with low or sometimes a normal ovarian reserve and is aggravated by advanced female age. These aspects will ultimately affect the number of embryos generated and consequently, the cumulative live birth rate. The novel system relies on female age, ovarian reserve markers, ovarian sensitivity to exogenous gonadotropin, and the number of oocytes retrieved, which will both identify the patients with low prognosis and stratify such patients into one of four groups of women with "expected" or "unexpected" impaired ovarian response to exogenous gonadotropin stimulation. Furthermore, the POSEIDON group introduced a new measure of clinical success in ART, namely, the ability to retrieve the number of oocytes needed to obtain at least one euploid blastocyst for transfer in each patient. Using the POSEIDON criteria, the clinician can firstly identify and classify patients who have low prognosis in ART, and secondly, aim at designing an individualized treatment plan to maximize the chances of achieving the POSEIDON measure of success in each of the four low prognosis groups. The novel POSEIDON classification system is anticipated to improve counseling and management of low prognosis patients undergoing ART, with an expected positive effect on reproductive success and a reduction in the time to live birth.

Keywords: ART calculator; POSEIDON criteria; assisted reproductive technology; blastocyst; low prognosis; oocyte; ovarian stimulation; poor ovarian response.

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The POSEIDON Criteria and Its Measure of Success Through the Eyes of Clinicians and Embryologists - PubMed

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This article represents a viewpoint on the POSEIDON criteria by a group of clinicians and embryologists. Its primary objective is to contextualize the Poseidon criteria and their metric of success for the relevant Frontiers Research Topic "POSEIDON's Stratification of Low Prognosis Patients in ART: ...

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Department of Reproductive Medicine, Dexeus University Hospital, Barcelona, Spain

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Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark

Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium

Poor ovarian responders represent one of the most difficult group of patients in every day clinical fertility practice. Still, a major limitation of the available published research is the striking diversity in the definitions used to define poor ovarian response, which could hamper the validity of the results ( 1, 2).

Despite the recent attempt by the European Society of Human Reproduction and Embryology (ESHRE) to apply a uniform definition for women who respond poorly to ovarian stimulation, the so called "Bologna" criteria ( 3), it seems that clinicians are still reluctant to use them in clinical studies ( 4), mainly due to the inability of these criteria to distinguish alterations in oocyte quantity vs. oocyte quality, grouping together women with different biologic characteristics and therefore altered clinical prognosis.

Recently, the POSEIDON group proposed a more detailed stratification of low responders, taking into account essential baseline characteristics of infertile women, which could have a significant impact on their reproductive outcome ( 5). In this context, patient classification is not only based on the number of oocytes retrieved, but also on various other features that may affect treatment success and should be carefully taken into consideration in the era of tailored-approach treatment, such as age and ovarian "sensitivity" to exogenous gonadotropins.

In this regard, four different patients' categories have been identified through the POSEIDON criteria, taking into account patients' age, ovarian reserve markers and response to stimulation in order to define patients' actual prognosis.

POSEIDON Group 1 apparently includes the best prognosis patients, compared to other POSEIDON groups, referring to young infertile women (<35 years old), with adequate ovarian reserve markers (AFC ≥ 5; AMH ≥ 1.2 ng/ml), and unexpected poor (<3 oocytes retrieved) or suboptimal (4-9 oocytes retrieved) response following conventional ovarian stimulation ( 5).

Management of women belonging to the POSEIDON group 1 requires a distinct diagnostic and therapeutic approach in relation to patients' characteristics, which should be specifically tailored to their young age and the adequate ovarian reserve of these women ( 6).

Age is undeniably the strongest determinant of treatment success in women seeking fertility advice ( 7). The age-related decline in fertility, owing to a significant decrease in both oocyte quantity (as reflected by lower oocyte yield) and quality (as reflected by higher aneuploidy and spontaneous abortion rates), is directly associated with the very low LBR observed in older women ( 8). Therefore, although prognosis is very bad in old poor responders, irrespective of the treatment modality used ( 9, 10), substantial benefit could be anticipated in younger women if an adequate number of oocytes is harvested. If we further consider that suboptimal response to stimulation significantly impairs cumulative live birth rates ( 11- 13) and that women with unexpected poor/suboptimal responders may have better prognosis compared to patients with predicted low response ( 14- 16), it could be stated that POSEIDON group 1 patients may represent the most interesting group, on which clinical research should focus in the future.

Several pathophysiological explanations have been proposed in order to clarify the nature of unexpected poor/suboptimal response. Ovarian sensitivity in relation to gonadotropin treatment has been the dominating theory, with evidence deriving from the investigation of the genetic variations of gonadotropins and their receptors ( 17). In particular, FSHR polymorphisms (e.g., Ser680Asn and Thr307Ala) have been associated with reduced sensitivity to gonadotropins ( 18) and may be the most reasonable explanation for the inadequate response following ovarian stimulation ( 19). This, in addition to the established need for higher gonadotropins in these patients ( 18), despite their normal ovarian reserve markers ( 20), suggests that genetic variation in the FSHR is a marker of ovarian sensitivity, irrespective of ovarian reserve.

On the other hand, a common variant of the β subunit of luteinizing hormone (LH) (v-LH) has been shown to affect FSH sensitivity and the ovarian response to FSH in normogonadotrophic women. Previous studies demonstrated that patients with this genetic variant of LH may experience an unexpected suboptimal response to stimulation and actually require higher cumulative-dose of gonadotropins ( 21, 22); thus, it may be imperative to consider the potential presence of such a genetic variant among several patients belonging to POSEIDON group 1.

Furthermore, less studied polymorphisms including FSH/LHCGR genes and their combinations may also be relevant, although evidence is sparse ( 23, 24).

Clear treatment guidelines have not been established for POSEIDON group 1 patients; still, this needs to be tailored in accordance to the underlying pathophysiological mechanism responsible for the impaired response to stimulation ( 6).

Utilization of higher gonadotropin doses of more "potent" recombinant formulations may be the solution in a significant percentage of these women, especially in the ones with polymorphisms identified in the FSHR gene. Taking into account that the Ser680Asn polymorphism of the FSHR gene may negatively influence the ovarian response to FSH stimulation and women with the genotype Ser/Ser appear to be more resistant to FSH action, a pharmacogenetic study demonstrated that treatment with higher FSH starting dose (225IU) in women homozygous for Ser680 (SS) resulted in similar serum estradiol (E2) levels with women who are homozygous for Asn680 (AA)/heterozygous (AS) treated with lower FSH doses (150IU) and significantly higher E2 levels compared to SS women treated with low 150IU dose ( 25). Moreover, a recent retrospective study evaluated the effect of FSH dose adjustment in women with a history of suboptimal response (4-9 oocytes retrieved) and demonstrated that an increase in the starting dose of FSH was significantly associated with a higher oocyte yield in the following IVF cycle ( 26).

On the other hand, administration of r-LH supplementation could be another option in these women, especially in cases of genetic variations of LH gene. Given the accumulating evidence from clinical research demonstrating that recombinant LH (rLH) could potentially increase the number of oocytes retrieved and result in higher pregnancy rates in women with non-pathological ovarian reserve tests and previous unexpected poor ( 27) or inadequate response ( 28), the use of rLH in these women is fully justified, and future research is essential to confirm these initial findings.

The utilization of novel promising approaches such a dual stimulation should not be overlooked and may be of benefit for POSEIDON group 1 patients. The rationale of this strategy is that poor prognosis women may undergo both follicular and luteal phase ovarian stimulation in the same menstrual cycle, in an attempt to maximize the number of oocytes retrieved and in turn increase the chance to obtain a genetically normal embryo in a short time interval ( 29). However, more evidence is needed for the applicability of luteal phase stimulation in poor responders, before implementation in clinical practice.

The synchronization of the follicular cohort through luteal phase estradiol/oral contraceptive pills (OCP) pre-treatment could be an option in young patients with unexpected poor or suboptimal response; albeit evidence extrapolated from studies in poor responders is controversial ( 2, 30).

Finally, adjuvant treatments with growth hormone (GH) or testosterone have been of great interest as an option to improve the outcome in women with a poor ovarian response and certainly merit evaluation in POSEIDON group 1. However, it should be stated that even if previous meta-analyses support the use of these regimens in poor responders ( 31, 32), results need to be interpreted with great caution due to limited evidence and small sample size of the relevant RCTs ( 33).

In conclusion, young women with normal ovarian reserve markers with a previous unexpected poor or suboptimal response seem to form a distinct group of infertile patients with different clinical prognosis compared to poor responders according to the "Bologna" criteria. Genetic polymorphisms of gonadotropins and their receptors may be a plausible explanation for the poor/suboptimal response following conventional ovarian stimulation; albeit more evidence is needed (NCT03007043, available at: clinicaltrials.gov). The management of these patients may imply the increase in the starting dose of recombinant FSH and/or supplementation with rLH or even double ovarian stimulation in an attempt to increase the number of oocytes retrieved and therefore the final reproductive outcome. The use of GH/testosterone and priming protocols including estradiol/OCPs represent other promising options. Nonetheless, further studies are warranted in order to validate these therapeutic approaches.

Author Contributions

NP and PD contributed equally to the design and the writing of the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

# data[].attributes.attachment_link.title
Management Strategies for POSEIDON's Group 1

# data[].attributes.attachment_link.description
Poor ovarian responders represent one of the most difficult group of patients in every day clinical fertility practice. Still, a major limitation of the available published research is the striking diversity in the definitions used to define poor ovarian response, which could hamper the validity of the results (Polyzos and Devroey, 2011; Polyzos and Tournaye, 2014).

# data[].attributes.attachment_link.readable_text
doi: 10.1186/s12958-019-0475-x.

Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy. confale@hotmail.it.

2 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

3 Department of Senology, Medical Oncology, National Cancer Institute, IRCCS "Fondazione G.Pascale", Naples, Italy.

4 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

5 Unit of Obstetrics and Gynaecology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

6 Istituto per l'Endocrinologia e l' Oncologia Sperimentale (IEOS) Consiglio Nazionale delle Ricerche, Naples, Italy.

Free PMC article

Alessandro Conforti et al. Reprod Biol Endocrinol.

Free PMC article

doi: 10.1186/s12958-019-0475-x.

Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy. confale@hotmail.it.

2 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

3 Department of Senology, Medical Oncology, National Cancer Institute, IRCCS "Fondazione G.Pascale", Naples, Italy.

4 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

5 Unit of Obstetrics and Gynaecology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

6 Istituto per l'Endocrinologia e l' Oncologia Sperimentale (IEOS) Consiglio Nazionale delle Ricerche, Naples, Italy.

Figures

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LH serum levels during ovarian stimulation as predictors of ovarian response and assisted reproduction outcome in down-regulated women stimulated with recombinant FSH.

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Understanding Ovarian Hypo-Response to Exogenous Gonadotropin in Ovarian Stimulation and Its New Proposed Marker-The Follicle-To-Oocyte (FOI) Index.

Alviggi C, Conforti A, Esteves SC, Vallone R, Venturella R, Staiano S, Castaldo E, Andersen CY, De Placido G. Alviggi C, et al. Front Endocrinol (Lausanne). 2018 Oct 17;9:589. doi: 10.3389/fendo.2018.00589. eCollection 2018. Front Endocrinol (Lausanne). 2018. PMID: 30386293 Free PMC article. Review.

References

Conforti A, Esteves SC, Di Rella F, Strina I, De Rosa P, Fiorenza A, Zullo F, De Placido G, Alviggi C. The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2019;17(18) 10.1186/s12958-019-0460-4. - PMC - PubMed

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Correction to: The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis - PubMed

# data[].attributes.attachment_link.description
doi: 10.1186/s12958-019-0475-x. 1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy. confale@hotmail.it. 2 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil. 3 Department of Senology, Medical Oncology, National Cancer Institute, IRCCS "Fondazione G.Pascale", Naples, Italy. 4 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

# data[].attributes.attachment_link.readable_text
doi: 10.1186/s12958-019-0460-4.

Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy. confale@hotmail.it.

2 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

3 Department of Senology, Medical Oncology, National Cancer Institute, IRCCS "Fondazione G.Pascale", Naples, Italy.

4 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

5 Unit of Obstetrics and Gynaecology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

6 Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) Consiglio Nazionale delle Ricerche, Naples, Italy.

Free PMC article

Free PMC article

doi: 10.1186/s12958-019-0460-4.

Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy. confale@hotmail.it.

2 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

3 Department of Senology, Medical Oncology, National Cancer Institute, IRCCS "Fondazione G.Pascale", Naples, Italy.

4 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

5 Unit of Obstetrics and Gynaecology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

6 Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) Consiglio Nazionale delle Ricerche, Naples, Italy.

Abstract

Objective: To study the role of recombinant human LH supplementation in women with hypo-response to ovarian stimulation.

Methods: We performed a systematic review and meta-analysis of prospective clinical trials in which recombinant FSH monotherapy protocols were compared with LH-supplemented protocols in hypo-responders. A search was conducted of the Scopus, MEDLINE databases without time or language restrictions. Primary outcome was clinical pregnancy rate.

Results: Significantly higher clinical pregnancy rates (odds ratio: 2.03, P = 0.003), implantation rates (odds ratio: 2.62, P = 0.004) and number of oocytes retrieved (weight mean differences: 1.98, P = 0.03) were observed in hypo-responders supplemented with recombinant LH versus hypo-responders who underwent FSH monotherapy. No differences in terms of mature oocytes or miscarriage rates were found between the two groups.

Conclusion: In conclusion, our analysis confirms that women with a hypo-response to exogenous gonadotropins might benefit from LH supplementation. However, more trials are required before a definitive conclusion can be drawn.

Keywords: Assisted reproductive technologies; Hypo-responders; In vitro fertilization; LH; Ovulation induction; Recombinant LH.

Conflict of interest statement

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Prof Alviggi reports personal fees and honoraria from Merck outside the submitted work. Prof. Esteves declares receipt of speaker's fees from Merck, Lilly, and Besins outside the present study. Dr. Conforti, Dr. Di Rella Dr. Strina, Dr. De Rosa, Dr. Fiorenza, Prof Zullo and Prof. De Placido have nothing to disclose.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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References

La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014;20:124-140. doi: 10.1093/humupd/dmt037. - DOI - PubMed

Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Human Reprod. 2011;26:1768-1774. doi: 10.1093/humrep/der106. - DOI - PubMed

Conforti A, Cariati F, Vallone R, Alviggi C, de Placido G. Individualization of treatment in controlled ovarian stimulation: myth or reality? Biochimica Clinica. 2017;41:294-305.

Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, et al. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. 2016;105:1452-1453. doi: 10.1016/j.fertnstert.2016.02.005. - DOI - PubMed

Devroey P, Fauser BC, Diedrich K. Approaches to improve the diagnosis and management of infertility. Hum Reprod Update. 2009;15:391-408. doi: 10.1093/humupd/dmp012. - DOI - PMC - PubMed

# data[].attributes.attachment_link.keywords[]
follicle stimulating hormone / therapeutic use*

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
The role of recombinant LH in women with hypo-response to controlled ovarian stimulation: a systematic review and meta-analysis - PubMed

# data[].attributes.attachment_link.description
doi: 10.1186/s12958-019-0460-4. 1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy. confale@hotmail.it. 2 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil. 3 Department of Senology, Medical Oncology, National Cancer Institute, IRCCS "Fondazione G.Pascale", Naples, Italy. 4 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

# data[].attributes.attachment_link.readable_text
doi: 10.3389/fendo.2018.00589.

Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

2 Istituto per l'Endocrinologia e l'Oncologia Sperimentale Consiglio Nazionale Delle Ricerche, Naples, Italy.

3 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

4 Unit of Obstetrics and Gynaecology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

5 Laboratory of Reproductive Biology, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Copenhagen, Denmark.

Free PMC article

Free PMC article

doi: 10.3389/fendo.2018.00589.

Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

2 Istituto per l'Endocrinologia e l'Oncologia Sperimentale Consiglio Nazionale Delle Ricerche, Naples, Italy.

3 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

4 Unit of Obstetrics and Gynaecology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy.

5 Laboratory of Reproductive Biology, Faculty of Health and Medical Sciences, University Hospital of Copenhagen, Copenhagen, Denmark.

Abstract

Hypo-responsiveness to controlled ovarian stimulation is an undervalued topic in reproductive medicine. This phenomenon manifests as a low follicles output rate (FORT) with a discrepancy between the relatively low number of pre-ovulatory follicles which develop following ovarian stimulation as compared to the number of antral follicles available at the start of stimulation. The pathophysiology mechanisms explaining the ovarian resistance to gonadotropin stimulation are not fully understood, but the fact that both hypo-responders and normal responders share similar phenotypic characteristics suggests a genotype-based mechanism. Indeed, existing evidence supports the association between specific gonadotropin and their receptor polymorphisms and ovarian hypo-response. Apart from genotypic trait, environmental contaminants and oxidative stress might also be involved in the hypo-response pathogenesis. The ratio between the number of oocytes collected at the ovum pick up and the number of antral follicles at the beginning of OS [Follicle to oocyte index (FOI)] is proposed as a novel parameter to assess the hypo-response. Compared with traditional ovarian reserve markers, FOI might reflect most optimally the dynamic nature of follicular growth in response to exogenous gonadotropin. In this review, we contextualize the role of FOI as a parameter to identify this condition, discuss the underlying mechanisms potentially implicated in the pathogenesis of hypo-response, and appraise possible the treatment strategies to overcome hyper-responsiveness to gonadotropin stimulation.

Keywords: POSEIDON criteria; assisted reproductive technology; follicle output rate; follicle to oocyte index; hypo-response; in vitro fertilization; ovarian stimulation; ovulation induction.

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References

Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. (2011) 26:1768-74. 10.1093/humrep/der106 - DOI - PubMed

Conforti A, Cariati F, Vallone R, Alviggi C, de Placido G. Individualization of treatment in controlled ovarian stimulation: myth or reality? Biochim Clin. (2017) 41:294-305. 10.19186/BC_2017.051 - DOI

La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update (2014) 20:124-40. 10.1093/humupd/dmt037 - DOI - PubMed

Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, Esteves SC, et al. . A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. (2016) 105:1452-3. 10.1016/j.fertnstert.2016.02.005 - DOI - PubMed

Devroey P, Fauser BC, Diedrich K. Approaches to improve the diagnosis and management of infertility. Hum Reprod Update (2009) 15:391-408. 10.1093/humupd/dmp012 - DOI - PMC - PubMed

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Understanding Ovarian Hypo-Response to Exogenous Gonadotropin in Ovarian Stimulation and Its New Proposed Marker-The Follicle-To-Oocyte (FOI) Index - PubMed

# data[].attributes.attachment_link.description
Hypo-responsiveness to controlled ovarian stimulation is an undervalued topic in reproductive medicine. This phenomenon manifests as a low follicles output rate (FORT) with a discrepancy between the relatively low number of pre-ovulatory follicles which develop following ovarian stimulation as compa ...

# data[].attributes.attachment_link.readable_text
doi: 10.3389/fendo.2018.00461.

Affiliations

1 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

2 Department of Surgery, University of Campinas (UNICAMP), Campinas, Brazil.

3 Faculty of Health, Aarhus University, Aarhus, Denmark.

4 ORIGEN, Center for Reproductive Medicine, Rio de Janeiro, Brazil.

5 Division of Reproductive Medicine, Department of Gynecology and Obstetrics, University of São Paulo, Ribeirão Preto, Brazil.

6 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

7 Fertility Clinic Skive Regional Hospital, Skive, Denmark.

Free PMC article

Sandro C Esteves et al. Front Endocrinol (Lausanne).

Free PMC article

doi: 10.3389/fendo.2018.00461.

Affiliations

1 ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil.

2 Department of Surgery, University of Campinas (UNICAMP), Campinas, Brazil.

3 Faculty of Health, Aarhus University, Aarhus, Denmark.

4 ORIGEN, Center for Reproductive Medicine, Rio de Janeiro, Brazil.

5 Division of Reproductive Medicine, Department of Gynecology and Obstetrics, University of São Paulo, Ribeirão Preto, Brazil.

6 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

7 Fertility Clinic Skive Regional Hospital, Skive, Denmark.

Abstract

Women with impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation present a challenge for reproductive specialists. The primary reasons relate to the still limited knowledge about the POR pathophysiology and the lack of practical solutions for the management of these conditions. Indeed, clinical trials using the current standards to define POR failed to show evidence in favor of a particular treatment modality. Furthermore, critical factors for reproductive success, such as the age-dependent embryo aneuploidy rates and the intrinsic ovarian resistance to gonadotropin stimulation, are not taken into consideration by the current POR criteria. As a result, the accepted definitions for POR have been criticized for their inadequacy concerning the proper patient characterization and for not providing clinicians a guide for therapeutic management. A novel system to classify infertility patients with "expected" or "unexpected" inappropriate ovarian response to exogenous gonadotropins-the POSEIDON criteria-was developed to provide a more nuanced picture of POR and to guide physicians in the management of such patients. The new standards are provoking as they challenge the current terminology of POR in favor of the newly defined concept of "low prognosis." This article provides readers a critical appraisal of the existing criteria that standardize the definition of POR and explains the primary reasons for the development of the POSEIDON criteria.

Keywords: POSEIDON criteria; assisted reproductive technology; hypo-responder; low responder; ovarian stimulation; poor ovarian reserve; poor ovarian response.

Figures

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References

Malchau SS, Henningsen AA, Loft A, Rasmussen S, Forman J, Nyboe Andersen A, et al. . The long-term prognosis for live birth in couples initiating fertility treatments. Hum Reprod. (2017) 32:1439-49. 10.1093/humrep/dex096 - DOI - PubMed

Haahr T, Roque M, Esteves SC, Humaidan P. GnRH agonist trigger and LH activity luteal phase support versus hCG trigger and conventional luteal phase support in fresh embryo transfer IVF/ICSI cycles-a systematic PRISMA review and meta-analysis. Front Endocrinol. (2017) 8:116. 10.3389/fendo.2017.00116 - DOI - PMC - PubMed

Haahr T, Esteves SC, Humaidan P. Poor definition of poor-ovarian response results in misleading clinical recommendations. Hum Reprod. (2018) 33:979-80. 10.1093/humrep/dey059 - DOI - PubMed

Haahr T, Esteves SC, Humaidan P. Individualized controlled ovarian stimulation in expected poor-responders: an update. Reprod Biol Endocrinol. (2018) 16:20. 10.1186/s12958-018-0342-1 - DOI - PMC - PubMed

Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. (2011) 26:1768-74. 10.1093/humrep/der106 - DOI - PubMed

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Defining Low Prognosis Patients Undergoing Assisted Reproductive Technology: POSEIDON Criteria-The Why - PubMed

# data[].attributes.attachment_link.description
Women with impaired ovarian reserve or poor ovarian response (POR) to exogenous gonadotropin stimulation present a challenge for reproductive specialists. The primary reasons relate to the still limited knowledge about the POR pathophysiology and the lack of practical solutions for the management of ...

# data[].attributes.attachment_link.readable_text
doi: 10.3389/fendo.2018.00361.

Affiliations

1 Department of Surgical and Clinical Science, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.

2 Center for Reproductive Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium.

3 Department of Reproductive Medicine, University of Liège, Liège, Belgium.

4 Department of Obstetrics, Gynaecology and Reproductive Medicine, Santa Maria University Hospital, Lisbon, Portugal.

5 Instituto Valenciano de Infertilidad (IVI-RMA), Valencia, Spain.

6 Instituto Valenciano de Infertilidad (IVI-RMA), Madrid, Spain.

7 Department of Obstetrics and Gynecology, Rey Juan Carlos University, Madrid, Spain.

8 Department of Obstetrics and Gynaecology, University of Zagreb-School of Medicine, Zagreb, Croatia.

9 Department of Reproductive Medicine, Dexeus University Hospital, Barcelona, Spain.

10 Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.

Free PMC article

Free PMC article

doi: 10.3389/fendo.2018.00361.

Affiliations

1 Department of Surgical and Clinical Science, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.

2 Center for Reproductive Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium.

3 Department of Reproductive Medicine, University of Liège, Liège, Belgium.

4 Department of Obstetrics, Gynaecology and Reproductive Medicine, Santa Maria University Hospital, Lisbon, Portugal.

5 Instituto Valenciano de Infertilidad (IVI-RMA), Valencia, Spain.

6 Instituto Valenciano de Infertilidad (IVI-RMA), Madrid, Spain.

7 Department of Obstetrics and Gynecology, Rey Juan Carlos University, Madrid, Spain.

8 Department of Obstetrics and Gynaecology, University of Zagreb-School of Medicine, Zagreb, Croatia.

9 Department of Reproductive Medicine, Dexeus University Hospital, Barcelona, Spain.

10 Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.

Abstract

Several infertile patients, who may even represent around 40% of the infertile cohort, may respond "suboptimally" (4-9 oocytes retrieved) following IVF, despite being predicted as normal responders. The aim of our longitudinal study was to evaluate the ovarian response of suboptimal responders in terms of the number of oocytes retrieved, following their second IVF cycle, evaluating exclusively patients who had the same stimulation protocol and used the same or higher initial dose of the same type of gonadotropin compared to their previous failed IVF attempt. Overall, our analysis included 160 patients treated with a fixed antagonist protocol in their second cycle with the same [53 (33.1%)] or higher [107 (66.9%)] starting dose of rFSH. The number of oocytes retrieved was significantly higher in the second IVF cycle [6 (5-8) vs. 9 (6-12), p < 0.001]. According to our results, a dose increment of rFSH remained the only significant predictor of the number of oocytes retrieved in the subsequent IVF cycle (coefficient 0.02, p-value = 0.007) after conducting GEE multivariate regression, while adjusting for relevant confounders. A regression coefficient of 0.02 for the starting dose implies that an increase of 50 IU of the initial rFSH dose would lead to 1 more oocyte.

Keywords: dose adjustments; number of oocytes; oocytes; ovarian response; suboptimal responders.

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References

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Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al. . Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. (2016) 31:370-6. 10.1093/humrep/dev316 - DOI - PubMed

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national center for biotechnology information

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The Effect of Dose Adjustments in a Subsequent Cycle of Women With Suboptimal Response Following Conventional Ovarian Stimulation - PubMed

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Several infertile patients, who may even represent around 40% of the infertile cohort, may respond "suboptimally" (4-9 oocytes retrieved) following IVF, despite being predicted as normal responders. The aim of our longitudinal study was to evaluate the ovarian response of suboptimal responders in te ...

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Impact of Maternal Age on Oocyte and Embryo Competence - PubMed

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The overall success of human reproduction, either spontaneously or after IVF, is highly dependent upon maternal age. The main reasons for age-related infertility include reduced ovarian reserve and decreased oocyte/embryo competence due to aging insults, especially concerning an increased incidence…

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doi: 10.3389/fendo.2018.00317.

Affiliations

1 Clinica Valle Giulia, G.en.e.r.a. Centers for Reproductive Medicine, Rome, Italy.

2 Clinica Ruesch, G.en.e.r.a. Centers for Reproductive Medicine, Naples, Italy.

3 G.en.e.r.a. Veneto, G.en.e.r.a. Centers for Reproductive Medicine, Marostica, Italy.

4 G.en.e.r.a. Umbria, G.en.e.r.a. Centers for Reproductive Medicine, Umbertide, Italy.

5 University of Targu Mures, Targu Mures, Romania.

Free PMC article

Free PMC article

doi: 10.3389/fendo.2018.00317.

Affiliations

1 Clinica Valle Giulia, G.en.e.r.a. Centers for Reproductive Medicine, Rome, Italy.

2 Clinica Ruesch, G.en.e.r.a. Centers for Reproductive Medicine, Naples, Italy.

3 G.en.e.r.a. Veneto, G.en.e.r.a. Centers for Reproductive Medicine, Marostica, Italy.

4 G.en.e.r.a. Umbria, G.en.e.r.a. Centers for Reproductive Medicine, Umbertide, Italy.

5 University of Targu Mures, Targu Mures, Romania.

Abstract

A panel of experts known as the POSEIDON group has recently redefined the spectrum of poor responder patients and introduced the concept of suboptimal response. Since an ideal management for these patients is still missing, they highlighted the importance of tailoring the ovarian stimulation based on the chance of each woman to obtain an euploid blastocyst. Interestingly, a novel pattern of follicle recruitment has been defined: multiple waves may arise during a single ovarian cycle. This evidence opened important clinical implications for the treatment of poor responders. For instance, double stimulation in the follicular (FPS) and luteal phase (LPS) of the same ovarian cycle (DuoStim) is an intriguing option to perform two oocyte retrievals in the shortest possible time. Here, we reported our 2-year experience of DuoStim application in four private IVF centers. To date, 310 poor prognosis patients completed a DuoStim protocol and underwent IVF with blastocyst-stage preimplantation-genetic-testing. LPS resulted into a higher mean number of oocytes collected than FPS; however, their competence (i.e., fertilization, blastocyst, euploidy rates, and clinical outcomes after euploid single-embryo-transfer) was comparable. Importantly, the rate of patients obtaining at least one euploid blastocyst increased from 42.3% ( n = 131/310) after FPS to 65.5% ( n = 203/310) with the contribution of LPS. A summary of the putative advantages and disadvantages of DuoStim was reported here through a Strengths-Weaknesses-Opportunities-Threats analysis. The strengths of this approach make it very promising. However, more studies are needed in the future to limit its weaknesses, shed light on its putative threats, and realize its opportunities.

Keywords: IVF; Poseidon; double stimulation; dual-stimulation; duostim; euploid blastocyst; low prognosis patients; poor responder.

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national center for biotechnology information

# data[].attributes.attachment_link.title
Double Stimulation in the Same Ovarian Cycle (DuoStim) to Maximize the Number of Oocytes Retrieved From Poor Prognosis Patients: A Multicenter Experience and SWOT Analysis - PubMed

# data[].attributes.attachment_link.description
A panel of experts known as the POSEIDON group has recently redefined the spectrum of poor responder patients and introduced the concept of suboptimal response. Since an ideal management for these patients is still missing, they highlighted the importance of tailoring the ovarian stimulation based o ...

# data[].attributes.attachment_link.readable_text
The management of patients with impaired or poor ovarian response (POR) remains a controversial and complex clinical issue. A systematic review of 47 randomized controlled trials revealed 41 different definitions of POR (

). Notably, the number of oocytes retrieved was adopted as a criterion of POR in 40% of the trials, although the threshold number differed considerably among studies (

). To standardize the definition of POR, Ferraretti et al. (

) proposed new criteria, known as the "Bologna criteria," based on three conditions: 1) advanced maternal age (≥40 years) or any other POR risk factor; 2) a previous incident of POR; and 3) a low ovarian reserve test in terms of antimüllerian hormone (AMH) and antral follicle count (AFC). Two of these three criteria are required for a POR diagnosis. In addition, two cycles with POR after maximal stimulation are sufficient to classify a patient as a poor responder even in the absence of the other criteria mentioned. Although the Bologna criteria were found to be useful in predicting the outcome of IVF and for counseling purposes, their use in clinical trials has been questioned because they entail the risk of grouping together women who differ significantly in biologic characteristics (

). For example, according to the Bologna criteria, young women with a low ovarian reserve associated with a previous episode of POR, young women with a normal ovarian reserve and two POR episodes, and older women (≥40 years) with a normal ovarian reserve and a previous episode of POR would be included in the same category even though the clinical management of these patients requires different strategies.

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References

A systematic review of randomized trials for the treatment of poor ovarian responders: is there any light at the end of the tunnel?.

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Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, Polyzos NP. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod 2016;31:370-376.

A common polymorphic allele of the LH beta-subunit gene is associated with higher exogenous FSH consumption during controlled ovarian stimulation for assisted reproductive technology.

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DOI: https://doi.org/10.1016/j.fertnstert.2016.02.005

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# data[].attributes.attachment_link.title
A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept

# data[].attributes.attachment_link.description
The management of patients with impaired or poor ovarian response (POR) remains a controversial and complex clinical issue. A systematic review of 47 randomized controlled trials revealed 41 different definitions of POR (1). Notably, the number of oocytes retrieved was adopted as a criterion of POR in 40% of the trials, although the threshold number differed considerably among studies (1).

# data[].attributes.attachment_link.readable_text
Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

2 Laboratory of Reproductive Biology, University Hospital of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.

3 Center for Gynecology, Endocrinology, and Reproductive Medicine, Ulm and Stuttgart, Germany.

4 Androfert, Andrology and Human Reproduction Clinic, Center for Male Reproduction, Campinas, São Paulo, Brazil.

5 Fertility Center Hamburg, Hamburg, Germany.

6 Department of Reproduction, Instituto Valenciano de Infertilidad, Barcelona, Spain, and Rome, Italy, and IVI Foundation, Valencia, Spain.

7 Center for Reproductive Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

8 Aberdeen Fertility Centre, Queen's Hospital, Barking, Havering and Redbridge University Hospitals, Essex, United Kingdom.

9 Genera, Center for Reproductive Medicine, Rome, Italy.

10 Fertility Clinic, Skive Regional Hospital, Skive, Denmark, and Faculty of Health, Aarhus University, Aarhus, Denmark.

Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) et al. Fertil Steril.

Affiliations

1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.

2 Laboratory of Reproductive Biology, University Hospital of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.

3 Center for Gynecology, Endocrinology, and Reproductive Medicine, Ulm and Stuttgart, Germany.

4 Androfert, Andrology and Human Reproduction Clinic, Center for Male Reproduction, Campinas, São Paulo, Brazil.

5 Fertility Center Hamburg, Hamburg, Germany.

6 Department of Reproduction, Instituto Valenciano de Infertilidad, Barcelona, Spain, and Rome, Italy, and IVI Foundation, Valencia, Spain.

7 Center for Reproductive Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

8 Aberdeen Fertility Centre, Queen's Hospital, Barking, Havering and Redbridge University Hospitals, Essex, United Kingdom.

9 Genera, Center for Reproductive Medicine, Rome, Italy.

10 Fertility Clinic, Skive Regional Hospital, Skive, Denmark, and Faculty of Health, Aarhus University, Aarhus, Denmark.

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# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept - PubMed

# data[].attributes.attachment_link.description
1 Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy. 2 Laboratory of Reproductive Biology, University Hospital of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark. 3 Center for Gynecology, Endocrinology, and Reproductive Medicine, Ulm and Stuttgart, Germany.

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L5 The periodic comet of POR: the novel POSEIDON classification

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1st Poseidon's World Conference: The Low-Prognosis Patient In ART9-10 September . Lisbon, Portugal

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The First POSEIDON's World Conference will dissect the new POSEIDON criteria as a means to improve the management of patients exposed to assisted reproductive technology. The new criteria enable discussion of novel approaches catered specifically to patients with low prognosis during IVF, thereby offering better tools to optimise IVF success rates.

The program will engage renowned international experts with vast clinical experience in constantly evolving subjects. The program aims to impart specific knowledge with focus on changing concepts or practices.

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This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.

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