In vitro fertilization–embryo transfer (IVF-ET) is an effective treatment for various causes of infertility. Ovarian stimulation is being used in the majority of assisted reproduction units in order to improve the success rate by increasing the number of oocytes and thus embryos available for transfer. Recruitment and development of multiple follicles in response to gonadotropin stimulation are the key factors leading to successful IVF treatment. Exaggerated ovarian responses, however, may lead to an increased risk of ovarian hyperstimulation syndrome (OHSS) Citation[1] and adverse outcomes of IVF treatment Citation[2].
Despite recent advances in the understanding of ovarian stimulation, gamete handling, the method of assisted fertilization and improved culture conditions, there has not been a significant increase in the implantation rates of cleaving embryos, which have remained steady at 20–25% for a long time. Herein we review the effects of excessive ovarian response on the pregnancy rate (PR) of IVF treatment and examine the possible mechanisms, including the quality of oocyte and embryos, the hormonal profile during the luteal phase and endometrial receptivity, which may lead to impairment in the PR of excessive ovarian responders.
Effects of excessive ovarian response on pregnancy rate
Detrimental effects
Forman and colleagues Citation[3] defined high serum estradiol (E2) as >90th percentile (2320 pg/ml) in 825 IVF cycles using gonadotropin with or without clomipehene for ovarian stimulation. There was a marked decrease in PR when E2 was >2320 pg/ml and only one or two embryos were transferred. However, similar PR was shown at all E2 levels after replacement of three embryos.
Simón and associates Citation[4] evaluated the effects of excessive ovarian response on the outcome of IVF cycles using a long protocol of pituitary downregulation. High responders with E2 >2500 pg/ml had a significantly lower PR than normal responders (16.4% vs. 33.3%; p < 0.05). Oocyte donation cycles were used to assess the embryo quality obtained from high responders who donated some of their oocytes in an oocyte-sharing program. In oocyte donation cycles, similar PR was noted in recipients of oocytes from high responders and normal responders. This suggested normal embryo quality from the high responder group. Simón's group Citation[5] further compared the step-down and standard stimulation protocols in the next IVF cycle of 86 high responders who had at least one previous failed IVF attempt with three to four good-quality embryos replaced and E2 >3000 pg/ml on the day of human chorionic gonadotropin (hCG) administration. This was not a randomized study as patients were voluntarily assigned to each treatment arm. The step-down group had significantly lower E2 and number of oocytes obtained but better PR (64.2% vs. 24.2%; p = 0.0002) compared with those receiving the standard protocol.
We reported the largest study of 1122 women aged <40 years using a standard long protocol of gonadotropin-releasing hormone (GnRH) agonist in their first IVF cycle Citation[2]. Serum E2 concentrations on the day of hCG were categorized into three groups: <10000 pmol/l (group A); 10 000–20 000 pmol/l (group B); and >20 000 pmol/l (group C). Women in group A had significantly fewer transfer cycles with three embryos replaced and a significantly lower PR per transfer compared with group B (16.2% vs. 23.7%; p = 0.005). Despite a similar number of transfers having three embryos replaced, the PR per transfer was significantly lower in group C than in group B (12.1% vs. 23.7%; p = 0.049).
A case report Citation[6] described a 38-year-old woman with 10 years of primary infertility and typical features of polycystic ovary syndrome who had exaggerated ovarian response. She underwent ten IVF cycles with 92 embryos replaced in stimulated cycles without success. In the 11th cycle, serum E2 concentration was 4512 pg/ml and 38 oocytes were obtained. ET was cancelled because of the high risk of OHSS. Subsequently, she conceived after frozen–thawed embryo transfer (FET) in a hormonal-replaced cycle. Yang and co-workers Citation[7] retrospectively investigated the effects of E2 per oocyte on the outcome of 251 IVF cycles with tubal transfer of embryos in 207 patients using a flare-up protocol and gonadotropin. Cycles with E2 per oocyte ≥350 pg/ml had significantly lower oocyte number and PR than those with <350 pg/ml. The authors suggested that poor outcome in cycles with E2 per oocyte ≥350 pg/ml was related to a detrimental effect of higher E2 (2213 vs. 1553 pg/ml; p = 0.037) on endometrial receptivity when compared with <350 pg/ml.
No detrimental effects
Chenette and co-investigators Citation[8] reported the outcome of 141 IVF cycles following a long protocol of pituitary downregulation and gonadotropin. E2 percentile ranges were divided into three groups: <1777 pg/ml, 1777–2777 pg/ml and >2777 pg/ml. Significantly higher PR was noted in the highest group (45%) than in the middle group (24%) and the lower group (14%). No pregnancies were encountered when E2 was >5000 pg/ml but there were only four patients with E2 >5000 pg/ml.
Sharara and McClarmrock Citation[9] addressed the effects of high ovarian responders in 106 patients undergoing the first IVF cycle after either a long or short protocol. High responders were defined as those with E2 >3000 pg/ml or the number of oocytes obtained >15. There was no difference in PR between normal and higher responders. E2 concentrations were further divided into four groups: ≤ 2000 pg/ml, 2001–2999 pg/ml, 3000–4000 pg/ml and >4000 pg/ml. No impairment in PR was noted in those with E2 >4000 pg/ml compared with the other groups.
The significance of E2 concentrations >5000 pg/ml has been evaluated in a case–control study of IVF cycles following a long protocol Citation[10]. Twenty-five patients with E2 >5000 pg/ml (range 5358–16 344 pg/ml) were compared with 25 controls with E2 <3500 pg/ml. The high responder group was associated with significantly more oocytes retrieved (21.4 ± 1.7 vs. 8.4 ± 0.6; p < 0.0001), fewer post-mature oocytes (1.6 ± 1.0% vs. 14.0 ± 5.0%; p < 0.03) and increased PR per transfer (62.0 ± 16.0% vs. 36.0 ± 16.0%; p < 0.01) compared with the control group.
Percentile E2 curves of 905 IVF cycles in 762 patients using a short protocol were used by Papageorgiou and colleagues Citation[11] to characterize the ovarian response. High responders were defined as those with E2 concentrations >90th percentile on day 5 and hCG day while poor responders were those with E2 <10th percentile. The mean E2 concentration in the high responder group was about 4000 pg/ml. The high responder group was associated with more embryos, better embryo quality and higher PR at all ages of patients.
In a systemic review Citation[12] of nine studies addressing the impact of serum E2 concentration on IVF outcomes, two studies (including 191 patients) suggested that the higher the E2 concentration on the day of hCG administration, the higher the probability of pregnancy. However, five studies (including 1875 patients) did not support an association between E2 concentrations on the day of hCG administration and PR. Moreover, two studies (including 1286 patients) suggested that high E2 levels on the day of hCG administration are associated with a decreased probability of pregnancy. The conclusion of the review was that there is no high-quality evidence to support or deny the value of E2 determination on the day of hCG administration for pregnancy achievement in IVF cycles where pituitary downregulation is performed with GnRH agonists. There is a need to perform well-designed prospective studies with adequate power.
Effects of excessive ovarian response on oocyte and embryo quality
Morphological assessment of oocytes and embryos remains the gold standard to determine oocyte and embryo quality in clinical assisted reproduction. Poor oocyte quality has been reported in patients with severe OHSS following stimulation Citation[13,14]. The percentage of good-quality oocytes (63.9% vs. 85.7%; p < 0.001) and fertilization rate (41.6% vs. 58.1%; p < 0.001) were significantly lower in patients with severe OHSS, compared with the control group, following stimulation for conventional IVF or intracytoplasmic sperm injection (ICSI) Citation[13]. The mean serum E2 concentration was 6700 ± 2350 pg/ml (mean ± standard deviation) in the OHSS group. There were no significant differences in the quality of embryos transferred and the implantation rate between the two groups. Similarly, Akagbosu and collaborators Citation[14] reported very poor fertilization rate following ICSI for severe male factors in a patient during the cycle complicated with OHSS, but normal fertilization rate in the subsequent cycle with a normal ovarian response.
In a self-controlled clinical study Citation[15], the oocyte quality, fertilization, implantation and pregnancy rates were not affected by the presence of severe OHSS in 22 patients who developed severe OHSS in the first cycle but had no OHSS in the second attempt. Coasting or withholding gonadotropin administration has been employed during ovarian stimulation to prevent excessive response and the development of OHSS. Oocyte and embryo quality were not compromised by coasting. The resulting PR was satisfactory after coasting but a coasting period of >4 days may be optimal for oocytes and embryos Citation[16].
There are only very few studies in the literature addressing oocyte and embryo quality in those with excessive ovarian response. Embryo quality from cycles with excessive ovarian response has been indirectly evaluated by the pregnancy outcome in an embryo cryopreservation program Citation[2],Citation[17] and an oocyte donation program Citation[4],Citation[18]. Using a logistic multiple regression analysis, Schalkoff and associates Citation[17] could not find any effect of serum E2 concentrations on the day of the hCG injection on the PR of 184 FET cycles, when these E2 concentrations were categorized as <3000 pg/ml or ≥3000 pg/ml.
In our study Citation[2], we followed the FET cycles in those who did not get pregnant in the stimulated IVF cycle. PR of the three groups in FET cycles was comparable. These data suggested that high serum E2 in stimulated IVF cycles adversely affects PR but embryo quality seems unaffected, as excess embryos from different groups had similar PR in FET cycles.
Oocyte donation seems to be an ideal model to study the effects of high E2 on oocyte/embryo quality and endometrial receptivity because the ovarian responses of oocyte donors are dissociated from the endometrial receptivity of the recipients. Pena and co-workers Citation[18] examined PR in 330 consecutive fresh oocyte donation cycles in which all donors were fertile. Peak E2 concentrations were grouped by 33rd percentile (group I: <1500 pg/ml; group II: 1500–3000 pg/ml; group III: >3000 pg/ml). There was no significant difference in the quality of oocytes obtained. Compared with group I, group III had significantly higher implantation rate (24.5% vs. 17.4%; p < 0.05). Groups II and III had significantly higher number of embryos available for transfer and cryopreservation compared with group I.
We carried out a retrospective analysis of oocyte and embryo quality in 278 women of age <40 years in their first ICSI cycle performed for severe male factors Citation[19]. Serum E2 levels on the day of hCG were again categorized into three groups: <10 000 pmol/l (group A), 10 000–20 000 pmol/l (group B) and >20 000 pmol/l (group C). The percentage of metaphase II oocytes (85%), fertilization rate (60–66%) and distribution of blastomere number per embryo were similar among the three groups. The proportion of transferable embryos was not reduced in group C compared with that of group A and group B.
Ovarian stimulation may affect aneuploidy in embryos Citation[20]. In a recent randomized controlled trial Citation[21] comparing a mild stimulation regimen of GnRH antagonist and a conventional high-dose gonadotropin and GnRH agonist, a significantly lower embryo aneuploidy rate was found following preimplantation genetic diagnosis in patients receiving mild stimulation. This study did not specifically evaluate the excessive ovarian responders and there are no details of serum E2 concentration after ovarian stimulation. Moreover, the possibility that different GnRH analogs directly influence the chromosomal constitution of the embryos cannot be ruled out.
Effects of excessive ovarian response on hormonal profile during the luteal phase
Progesterone (P) in the luteal phase is essential for implantation. The role of E2 in the luteal phase is, however, unclear and it is suggested that it plays only a permissive rather than an obligatory role. There is little recent information in humans with regard to the importance and necessity of luteal E2 during stimulated cycles in patients undergoing IVF-ET. Luteal-phase serum E2 and P concentrations were not related to the outcome of IVF treatment Citation[22]. On the other hand, several groups Citation[23-25] have found significantly higher E2 levels during the mid-luteal period in pregnant than non-pregnant cycles. Higher E2 levels in the luteal phase may reflect better ovarian response in the follicular phase. Moreover, different luteal supports including no support, hCG and P were employed and this may explain the different results observed in these studies. Pituitary downregulation was also not used in these studies.
Menopausal or functionally agonadal women could achieve donor oocyte pregnancies without the support of E2 in the luteal phase Citation[26-28]. The permissive function of luteal E2 in humans was also suggested by the examination of endometrial development. Mid-luteal endometrial morphology of glandular and stromal elements was not significantly affected by the cessation of E2 treatment and the reduction of E2 concentration to hypogonadic levels in the luteal phase after an adequate follicular priming Citation[29,30]. Endometrial maturation assessed by estrogen and progesterone receptors showed the typical distribution of the normal mid-luteal endometrium in those patients with and without E2 supplementation in the luteal phase Citation[29].
The magnitude of decline in E2 concentration after oocyte retrieval may be more important than the absolute value of E2 in the luteal phase. Sharara and McClamrock Citation[31] found an adverse outcome in 106 patients undergoing the first IVF-ET cycle using P in the luteal phase when the ratio of day-of-hCG E2 to mid-luteal E2 (E2 ratio) was >5. Ongoing PR in those with E2 ratio of >5 was 15.8%, compared with 42.1% with E2 ratio of 0.4–2.5 and 53.3% with E2 ratio of 2.5–5.0. It was postulated that impaired endometrial receptivity might be compromised by a rapid decline in E2 concentrations in the luteal phase, i.e. a high E2 ratio.
We performed a retrospective analysis of 763 women of age <40 years undergoing their first IVF cycle and replacing three or fewer embryos Citation[32]. In cycles receiving hCG for luteal support, 25th, 50th and 75th centiles of E2 ratio were 1.8, 2.8 and 5.0 respectively. Hormonal parameters were not different between pregnant and non-pregnant cycles. The outcomes were similar irrespective of the E2 ratio. P supplementation was instead used when the day-of-hCG E2 was >18 000 pmol/l or there were features of OHSS. PR of these hyperstimulated cycles was 16.7% and 11.4% per cycle respectively when E2 ratio was ≤ 5.0 and >5.0. This difference did not reach statistical significance. Therefore, our results could not find an adverse outcome in cycles showing a rapid decline in E2 during the mid-luteal phase.
Effects of excessive ovarian response on endometrial receptivity
Successful implantation depends on the dialogue between a good-quality blastocyst and a receptive endometrium. Different strategies have been developed to evaluate endometrial receptivity, such as ultrasound examination of the endometrium Citation[33,34], the histological dating of an endometrial biopsy Citation[35], endometrial cytokines in uterine flushing Citation[36] and the genomic study of a timed endometrial biopsy Citation[37].
Little information exists in the literature regarding the effects of excessive ovarian response on endometrial development, secretion of endometrial proteins or ultrasound parameters of endometrial receptivity. The majority of published studies addressed the effects of ovarian stimulation on endometrial histology and endometrial steroidal receptors. Differences in the selection of patients, ovarian stimulation regimens, the timing of endometrial biopsy and histological dating methods among these studies make it very difficulty to draw any firm conclusion.
Peri-implantation endometrial development by morphometry
We have examined the effects of excessive ovarian response on peri-implantation endometrial development using morphometric analysis of the glandular and stromal components of an endometrial biopsy taken on day 7 after the ovulating dose of hCG injection in stimulated cycles and on day 7 after the LH surge in natural cycles Citation[38]. Excessive ovarian responders, i.e. serum E2 >20 000 pmol/l on the day of hCG, showed delayed glandular maturation and advanced stromal morphology; whereas moderate responders, i.e. serum E2≤ 20 000 pmol/l, demonstrated synchronous glandular and stromal development. In natural cycles, glands were in phase. A deficient secretory transformation of the endometrium in the excessive responders may lead to a suboptimal endometrial environment for implantation.
Doppler study of uterine vessels during the peri-implantation period
On the day of ET we measured color Doppler indices of utero-ovarian arteries and endometrial color signals in 58 women undergoing ovarian stimulation for IVF Citation[39]. They were classified according to serum E2 concentrations on the day of hCG injection into moderate responders (E2 <20 000 pmol/l; n = 39) and high responders (E2≥20 000 pmol/l; n = 19). Uterine arterial pulsatility index (PI) and resistance index (RI) were significantly lower in high responders than in moderate responders. The number of women showing endometrial color signals was significantly lower in high responders than in moderate responders. A further increase in E2 (≥25 000 pmol/l; n = 8) showed significantly fewer endometrial color signals compared with moderate responders [1.5 (0–8) vs. 4 (0–14) respectively; p = 0.03]. Despite low uterine PI and RI, the endometrial blood flow in high responders appeared to be impaired. This may contribute to the decline in implantation efficiency noted in high responders.
Endometrial blood flow measured by three-dimensional ultrasound
A good blood supply towards the endometrium is usually considered an essential requirement for successful implantation. Endometrial blood flow can now be non-invasively evaluated by three-dimensional (3D) ultrasound with power Doppler Citation[40]. 3D ultrasound examination with power Doppler was performed 2, 4 and 7 days after hCG in 32 patients who did not have ET to measure endometrial thickness, PI/RI of uterine vessels, endometrial volume and 3D power Doppler flow indices of endometrial and sub-endometrial regions Citation[41]. Changes in uterine Doppler flow indices, endometrial and sub-endometrial 3D power Doppler flow indices during the early luteal phase were significantly different between moderate and excessive responders.
Cytokine expression of peri-implantation endometrium
We further evaluated in vivo expression of T helper type 1 (Th1) and type 2 (Th2) cytokines in the peri-implantation endometrium of infertile patients between natural and stimulated cycles Citation[42,43]. Uterine flushings and endometrial biopsies were collected 7 days after the LH surge in natural cycles or after hCG injection in stimulated cycles. When compared with moderate responders or those in natural cycles, interleukin (IL)-2 was significantly increased and IL-11 and IL-6 concentrations were significantly decreased in peri-implantation endometrium from excessive responders. This imbalance between over-expressed Th1 and under-expressed Th2 cytokines may lead to an adverse endometrial environment in excessive ovarian responders.
Gene expression profiling of peri-implantation endometrium
High serum E2 and/or P concentrations may also affect the gene expression profiles of human peri-implantation endometrium Citation[44]. Clustering and principal component analysis demonstrated a significant difference (≥2-fold) in the expression patterns of 411 genes among the above three groups. Putative estrogen-responsive elements or progesterone-responsive elements were identified in the promoter regions of 49 differentially expressed genes of diverse functions.
Conclusion
Excessive ovarian responses may impair IVF outcomes. The oocyte and embryo quality seem unaffected by serum E2 in the stimulated cycle. Endometrial development in excessive responders is associated with a deficient secretory transformation, imbalance between over-expressed Th1 and under-expressed Th2 cytokines, dysregulated gene expression, and changes in endometrial blood flow at the time of peri-implantation period. These changes may impair endometrial receptivity.
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