Lower Risk Of Ovarian Hyperstimulation Syndrome Research Articles

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (Star, Cyp11a1, Cyp17a1) and genes involved in ovulation regulation (Adamts-1, Cox-2, Egr-1, Mt-1); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.

Ovulation triggering with hCG alone, GnRH agonist alone or in combination? A randomized controlled trial in advanced-age women undergoing IVF/ICSI cycles.

Is a dual ovulation trigger with a combination of GnRH agonist (GnRHa) and hCG superior to single hCG and/or single GnRHa trigger in improving treatment outcomes in advanced-age women (aged ≥ 35 years) undergoing IVF/ICSI treatment? Co-administration of GnRHa and hCG as a dual trigger increases the number of good-quality embryos but it is not associated with a higher number of oocytes retrieved, compared with single hCG or GnRHa trigger. Many studies have demonstrated that a dual trigger has positive impact on oocyte maturation, retrieval rate and pregnancy rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS) in some groups of IVF patients, when compared with single hCG trigger. Few studies have however been conducted to compare a dual trigger with a single GnRHa trigger, and insufficient evidence exists to support which trigger can achieve the best outcomes in IVF patients aged ≥35 years. This was an open-label randomized controlled trial of 510 participants conducted at single reproductive medical center from January 2019 to December 2021. After a sample size calculation performed by retrospectively analyzing our previous clinical data, we planned to recruit 170 patients in each group and 510 patients in total for the study. Women aged ≥35 years undergoing IVF/ICSI treatment, receiving a non-pituitary down-regulation protocol, and with low risk of OHSS, were enrolled in this trial. On the trigger day, patients were randomized into three groups: hCG alone (who received 6000 IU of hCG), GnRHa alone (who received 0.2 mg of triptorelin) and dual trigger (who received 0.2 mg of triptorelin plus 2000 IU of hCG) groups. The primary outcome parameter was the number of retrieved oocytes. The secondary outcome parameters included, among others, the number and rates of mature oocytes, two pronuclei (2PN) embryos and good-quality embryos, as the rates of OHSS, clinical pregnancy, miscarriage and live birth. There were no significant differences in the baseline demographic characteristics among the three groups. The dual trigger was associated with a higher retrieval rate (87.9% vs 84.1% in the hCG group, P = 0.031; 87.9% vs 83.6% in the GnRHa group, P = 0.014). However, the number of retrieved oocytes in the dual trigger group was comparable with those in the hCG group (4.08 ± 2.79 vs 3.60 ± 2.71, P = 0.080) and the GnRHa group (4.08 ± 2.79 vs 3.81 ± 3.38, P = 0.101); comparable data between the groups were also found when analyzing the number of 2PN embryos and the 2PN rate. In the dual trigger group, the numbers of good-quality embryos and viable embryos were both significantly higher than in the hCG group (1.74 ± 1.90 vs 1.19 ± 1.45, P = 0.016 and 2.19 ± 2.11 vs 1.56 ± 1.66, P = 0.008, respectively) and the GnRHa group (1.74 ± 1.90 vs 1.20 ± 1.67, P = 0.003 and 2.19 ± 2.11 vs 1.45 ± 1.75, P = 0.001, respectively). Pregnancy outcomes after fresh embryo transfer (ET) were comparable between the groups. The live birth rate and ongoing pregnancy rate after frozen ET in the dual trigger group were significantly higher than those in the GnRHa group (32.6% vs 14.1%, P = 0.007 and 34.8% vs 17.6%, P = 0.013, respectively), but not superior to those in the hCG group (32.6% vs 27.9%, P = 0.537 and 34.8% vs 27.9%, P = 0.358, respectively). Women of advanced age are quite a heterogeneous population and overlap with poor ovarian responders or patients with diminished ovarian reserve. We therefore could not entirely exclude selection biases or confounding factors. This study was also not a double-blinded trial; the patients in the GnRHa and dual trigger groups could have been affected by the placebo effect. The results of this study suggest that in advanced-age women with low risk of OHSS, a dual trigger or even a single hCG trigger may be a better choice than a single GnRHa trigger. This study was supported by the Shanghai Municipal Health Commission of Science and Research Fund (20184Y0289). The authors declare no conflict of interest. This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-1800016285). 24 May 2018. 2 January 2019.

Does HCG Luteal Support Improve Pregnancy Rates in GnRH Antagonist IVF Cycles and GnRH Agonist Trigger? A Randomized Controlled Trial

Background: Ovarian hyperstimulation syndrome (OHSS) remains one of the most serious complications in IVF cycles. hCG the gold standard for ovulation trigger carries the risk of initiating the cascade of events leading to OHSS, especially in patients with high ovarian response. In patients undergoing IVF using the GnRH antagonist protocol with GnRH agonist trigger instead of hCG there is a lower risk of OHSS but on the expense of a lower pregnancy rate than patients receiving the traditional hCG trigger. Aim of work: To evaluate whether a single dose of hCG 1500 units given to patients using the GnRH agonist trigger would improve pregnancy rates, without increasing the risk of OHSS. Patient and Methods: This is a randomized controlled trial, set in Adam International IVF Hospital from December 2014 till June 2015. 154 patients undergoing IVF using the GnRH antagonist protocol and triggered with GnRH agonist. Administering a single dose of hCG 1500 units immediately after ovum pick-up, compared to no hCG. Main outcome measure is chemical pregnancy rate. Other outcome measures include clinical pregnancy rate and incidence of OHSS. Results: There was a significant difference in chemical and clinical pregnancy rates (58.8% vs 35.9%, P 0.0485, 51.6% vs 20.0%, P 0.0001) in favour of intervention. No cases of severe OHSS were recorded in either groups. Conclusion: Giving a single dose of hCG 1500 units immediately after ovum pick-up significantly improves pregnancy rates without increasing the incidence of severe OHSS. The trial was registered with Pan African Clinical Study Registry (www.pactr.org), no. PACTR201512000952372.

Is oocyte maturity influenced by ovulation trigger type in oocyte donation cycles?

The aim of this study was to compare clinical and laboratory outcomes between GnRHa, dual and HCG triggers in altruistic oocyte donation cycles. Normal or high responders were given either gonadotropin releasing hormone agonist (GnRHa) or a dual trigger of GnRHa and a low dose of human chorionic gonadotropin (HCG). Low responders were given HCG trigger. In 333 cycles, 232 (69.7%) received GnRHa trigger, 59 (17.7%) received dual trigger and 42 (12.6%) had HCG trigger. The total number of mature oocytes retrieved and cryopreserved were significantly higher in the GnRHa and dual trigger groups, compared to the HCG group (p < 0.001). However, the ovarian hyperstimulation syndrome (OHSS) rate was significantly higher in the dual trigger group (n = 5 (8.5%)), compared to the GnRH agonist (n = 1 (0.4%)) and HCG groups (n = 0 (0%)) (p = 0.001). GnRHa trigger maximises mature oocyte yields in oocyte donors suspected of normal and high response but offers a significant reduction in OHSS risk compared to dual trigger. As such, dual trigger should not be used in oocyte donation. HCG trigger can also be used with a very low risk of OHSS at low risk of OHSS in carefully selected donors where GnRHa is unlikely to be effective.

GNRH agonist versus HCG to induce final oocyte maturation in patients at low risk of OHSS

Ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol offers the flexibility of utilizing a GnRH agonist (GnRHa) or hCG trigger for final oocyte maturation. When the follicle number or estradiol (E2) concentration is low, an hCG trigger may be selected if it is determined that the patient is at low risk of ovarian hyperstimulation syndrome (OHSS). It is unclear whether a GnRHa or hCG trigger in this clinical scenario yields superior outcomes.

Low dose HP-hMG in an antagonist protocol for IVF in ovulatory and anovulatory patients with high AMH

Women with high-AMH levels have an increased risk of ovarian hyperstimulation syndrome (OHSS). Studies have suggested that highly purified menotropin (HP-hMG) Menopur® reduces the risk. We, therefore, studied use of low-dose (112.5 IU/day) HP-hMG in ovulatory and anovulatory patients with high AMH (>32 pmol/L). The primary endpoint was the distribution of patients with appropriate, excessive, and inadequate response (5–14, ≥15, and ≤4 oocytes). Another endpoint was frequency of OHSS. Totally 115 women were included and 78 (67.8%) had an appropriate, 8 (7.0%) an excessive, and 29 (25.2%) an inadequate response. The number of oocytes was independent on AMH levels and ovulatory status but declined significantly with increasing bodyweight (R 2 = 0.07, p < .01). The ongoing pregnancy rate per started cycle was 47.0%. Three (2.6%) developed OHSS, two had cancelation of the cycle and seven patients had GnRH agonist triggering to prevent OHSS. Selective use of a low dose of HP-hMG in patients with high levels of AMH provides 5–14 oocytes in more than two-thirds of the patients and is safe with low risk of OHSS. The number of aspirated oocytes was independent of AMH levels and ovulatory status, but inversely related to body weight.

Fresh versus Frozen Embryo Transfer in PCOS: Arguments for and Against.

AbstractIn vitro fertilization (IVF) is a common infertility treatment for women with polycystic ovarian syndrome (PCOS) who have failed to conceive in ovulation induction and who have other concomitant infertility factors. Women with PCOS tend to have an excess response to ovarian stimulation during IVF. Freeze-all strategy with deferred frozen embryo transfer was initially used to prevent ovarian hyperstimulation syndrome (OHSS) in patients with a high risk. New evidence from randomized trials showed elective frozen embryo transfer in PCOS women with a low risk of OHSS could also lower the incidence of OHSS, improve live birth rate mainly by decreasing pregnancy loss, and increase birth weight of singleton infants compared with fresh embryo transfer. However, the risk of preeclampsia was higher after frozen than fresh embryo transfer. Observational studies and limited randomized trials showed the risks of other obstetric outcomes and long-term safety profile after frozen embryo transfers were at least as good as that after fresh embryo transfer. Summarily, current evidence showed elective freeze-all and frozen embryo transfer is generally superior to fresh embryo transfer to achieve live birth in women with PCOS; however, its effect on obstetric outcome and long-term outcome warrants further studies.

In-vitro maturation versus IVF with GnRH antagonist for women with polycystic ovary syndrome: treatment outcome and rates of ovarian hyperstimulation syndrome

In-vitro maturation (IVM) treatment has gained popularity for decreasing the incidence of ovarian hyperstimulation syndrome (OHSS) by eliminating or minimizing the use of gonadotrophins in women with polycystic ovary syndrome (PCOS). Studies have shown that IVF with GnRH-antagonist protocol is associated with a lower incidence of OHSS. Data comparing the relative success of these two treatments is, however, lacking. Treatment outcome and rates of OHSS were compared in patients with PCOS who underwent assisted conception with either IVM or IVF with GnRH-antagonist protocol between 2006 and 2011. The number of oocytes retrieved was higher in the IVM group, whereas the number of mature oocytes, fertilization rate and number of embryos cleaved were comparable. The implantation rate was higher in the IVF group. The clinical pregnancy rates per embryo transfer were not statistically different (IVF: 45.8% versus IVM: 32.4%). The live-birth rate was higher in the IVF group (IVF: 40.7% versus IVM: 23.5%; P = 0.04). Five women developed moderate or severe OHSS in the IVF group, whereas none did in the IVM group. Both IVM and IVF with GnRH-antagonist protocol seem to be effective treatment regimens in women with PCOS, although IVM is associated with a lower risk of OHSS.

GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients

Does a GnRH agonist (GnRHa) trigger followed by a bolus of 1.500 IU hCG in a group of patients at risk of ovarian hyperstimulation syndrome (OHSS) reduce the OHSS incidence compared with hCG trigger? A GnRHa trigger followed by early luteal hCG support with one bolus of 1.500 IU hCG appears to reduce OHSS in patients at risk of OHSS; however, in a low-risk group a second bolus of 1.500 IU hCG induced two cases of late onset OHSS. A GnRHa trigger is an alternative to hCG in GnRH antagonist co-treated cycles. Two RCTs were performed in four Danish IVF units. A total of 446 patients were assessed for eligibility and 390 patients were enrolled in the study from January 2009 until December 2011. The primary outcome of the study was OHSS incidence in the group at risk of OHSS. Patients received a fixed dose of recombinant human FSH for the first 4 days. On the day of triggering, patients were assessed for their risk of OHSS based on the total number of follicles ≥11 mm diameter, and were classified as being at risk of OHSS when the total number of follicles ≥11 mm was between 15 and 25 and at low risk of OHSS when the total number of follicles ≥11 mm was ≤14. Two separate randomization lists were used for each of the OHSS risk groups. Women at risk of OHSS were allocated (RCT 1) to either: Group A (n = 60), ovulation triggering with a bolus of 0.5 mg buserelin (GnRHa) s.c. followed by a single bolus of 1.500 IU hCG s.c. after the oocyte retrieval-or: Group B (n = 58): 5.000 IU hCG. Similarly, women at low risk of OHSS were allocated (RCT 2) to receive either: Group C (n = 125), a bolus of 0.5 mg buserelin s.c., followed by a bolus of 1.500 IU hCG s.c. after oocyte retrieval and a second bolus of 1.500 IU hCG on the day of oocyte retrieval +5-or: Group D (n = 141), 5.000 IU hCG. Groups C and D were included in order to obtain preliminary data. In women at risk of OHSS (RCT 1) (15-25 follicles) no OHSS case was seen in Group A (GnRHa trigger and one bolus of 1.500 IU hCG), whereas two cases of moderate late-onset OHSS occurred in group B (3.4%), (P = 0.24). In contrast, in women at a low risk of OHSS (RCT 2) (≤14 follicles) two cases of late-onset OHSS occurred in Group C (GnRHa trigger and two boluses of 1.500 IU hCG), whereas no OHSS case was encountered in Group D (P = 0.22). Although the first RCT was powered to include 168 patients at risk of OHSS (15-25 follicles ≥11 mm) randomized to either GnRHa trigger or hCG trigger, the trial was prematurely discontinued when a total of 118 patients at risk of OHSS were randomized. In addition the second RCT in the OHSS low-risk group was designed as a feasibility study to assess the incidence of OHSS after GnRHa trigger and dual hCG administration versus 5.000 IU hCG. No power calculation was performed for this trial. In addition, there was a lack of blinding in the RCTs. Although a non-significant result, one bolus of 1.500 IU hCG after GnRHa trigger tended to reduce the OHSS rate in patients with 15-25 follicles ≥11 mm as well as secure the ongoing pregnancy rate. In contrast, in patients at low risk of OHSS the administration of two boluses of 1.500 IU hCG after GnRHa trigger should be avoided as it may induce OHSS.

Agonist and antagonist coast

The use of GnRH-a in ovarian stimulation permitted stronger stimulation resulting in an increased incidence of OHSS. The first Cochrane review comparing GnRH agonist and GnRH antagonist protocols for ovarian stimulation showed no significant difference in OHSS rate between the two protocols, however, a recent Cochrane review showed a highly significant decrease in the incidence in OHSS rate in the antagonist protocol. Coasting is a commonly used procedure for preventions of OHSS. The optimum time to start coasting is when the lead follicle reaches 16 mm in diameter and hCG should be given when E2 level drops below 3000 pg/ml. Coasting may act by diminishing the functioning granulosa cell cohort. Administration of daily GnRH antagonist in high risk patients for OHSS who were down-regulated by GnRH-a resulted in rapid drop of E2 and decrease in incidence of OHSS. A series of patients who developed early OHSS were treated by daily GnRH antagonist injections, all embryos were cryopreserved. No progression to severe OHSS was observed.

Prevention of OHSS

Ovarian hyperstimulation syndrome (OHSS) is a major complication of ovulation induction. As the treatment of the syndrome is currently empirical, prevention is the most important aspect of its management. Identification of patients vulnerable to developing OHSS by taking a history of previous OHSS and polycystic ovarian syndrome is the first step in prevention. The use of mild stimulation protocols with small doses of gonadotrophin is also important. As gonadotrophin-releasing hormone (GnRH) antagonist protocol is associated with a lower risk of OHSS, antagonist could be the protocol of choice in high-risk patients. Withholding human chorionic gonadotrophin (HCG) and continuation of GnRH agonist will abort the syndrome but at the expense of loss of the cycle. Coasting, which involves stoppage of gonadotrophins until oestradiol drops to a low concentration before HCG injection, is an effective technique but it does not completely prevent OHSS. Intravenous albumin is useful in the prevention when given at time of oocyte retrieval. Cryopreservation of all embryos will reduce late-onset OHSS but not early-onset OHSS. In-vitro maturation of oocytes will avoid ovarian stimulation and totally prevent OHSS. Triggering ovulation with a lower dose of HCG is effective in reducing the incidence of OHSS. There are possible roles for metformin and dopamine agonist for prevention of OHSS.

An hCG Antagonist Reduces Ovulation and Diminishes OHSS in a Rodent Model

An hCG Antagonist Reduces Ovulation and Diminishes OHSS in a Rodent Model

Early estradiol in egg donor cycles is a good predictor of ovarian response and risk of ovarian hyperstimulation syndrome

To assess prognostic value of serum estradiol (SE) on day 4 of controlled ovarian stimulation (COS) in the first cycle of eggs donors referred to the ovarian response and risk of ovarian hyperstimulation syndrome (OHSS). Retrospective study of first eggs donor cycles from January 2005 to December 2006. The SE was evaluated on day 4 of COS with short protocol with an agonist of GnRH in 409 cycles of egg donors. Determined as Group A (low response), N = 81 (19, 80%) made up of 64 cycles (15, 64%) cancelled due to hypo-response plus 17 cycles (4, 15%) in which less than 6 MII oocytes were obtained. Determined as Group B (normal response), N = 328 cycles (80, 19%) in which 6 o more MII oocytes were obtained. Out of 409 cycles, only on 345 cycles (84, 36%) transvaginal oocyte retrieval was performed, 64 cycles (15, 64%) were cancelled. These 345 cycles were divided into : Group I (high risk of OHSS) N = 30 in cycles with SE on the day of HCG greater than 4000 pg/ml and Group II (low risk of OHSS) N = 315 (91, 31%) when the SE on the day of HCG was less than 4000 pg/ml. Statistical analysis was done by chi square and ANOVA. The SE on day 4 of the COS of Group A and B was 175,82 pg/ml ± 154,33 vs. 309,96 pg/ml ± 198,01 respectively with a P=0.001, which is statistically significant. If we would have considered a value of 65 pg/ml.of SE on day 4 of the COS as an indicator of cycle cancellation for low response, we could have decreased the percentage of donors that continued the COS and was cancelled later on for hypo response or the donors with less than 6 MII oocytes, from 19,80% to 14,18%. The SE on day 4 of the COS of Group I and II was 456,16 pg/ml. ± 245,10 vs. 294,34 pg/ml ± 189,65 respectively, with a P=0,001, which is statistically significant. A value of 320 pg/ml of SE on day 4 of COS is a good predictor as high risk of OHSS. The SE on day 4 of COS of egg donors who perform a short protocol with an agonist of GnRH is a good predictor of the cancellation rate due to low response, of low retrieval of mature oocytes and of risk of OHSS. With a value of SE less than 65 pg/ml it is advised to cancel the cycle, which would allow to anticipate the cancellation of the cycle with hypo response or decrease the number of cycles with less than 6 MII oocyte. A value of SE more than 320 pg/ml is a good predictor of high risk of OHSS.

Ovarian hyperstimulation syndrome is predicted by HCG serum concentration following the ovulatory dose of HCG

Background and Significance: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovarian stimulation therapy. The severe form is rare, with a reported incidence of 0.5 to 5%. Human chorionic gonadotropin (hCG) is routinely used to induce oocyte maturation and may be a risk factor for development of OHSS. Objective: The purpose of this retrospective study was to evaluate the relationship between serum hCG concentration the day after ovulatory dose of hCG and the subsequent occurrence of OHSS. Materials and Methods: Following ovarian stimulation, hCG was administered via intramuscular injection. Doses varied from 2,500 to 20,000 IU, based on each patient’s weight, age, estradiol concentration, and follicle count. Serum hCG concentrations were measured 12 to 16 hours after injection. Mild OHSS was defined as a constellation of symptoms, including intractable nausea, abdominal distension, vomiting, or diarrhea requiring office visit evaluations. Severe OHSS was defined as a progression of illness accompanied by one or more of the following: tense ascites requiring aspiration, laboratory abnormalities, progressive oliguria, and respiratory difficulty. Logistic regression was used to evaluate the effect of follicle count and hCG serum concentration following the ovulatory dose on the probability of occurrence of OHSS. Results: The study group included 877 IVF cycles that received ovulatory hCG dose between January, 1998 and August, 2003 at a private infertility clinic. Serum concentrations of hCG the day after ovulatory dose ranged from 37 to 731 IU/L, with a mean of 172 IU/L. The study group included 27 cases of OHSS, of which 12 were severe. Follicle count (p<0.0001) and hCG serum concentration (p=0.02) were significant predictors of OHSS (including both mild and severe cases). Similarly, follicle count (p<0.0001) and hCG serum concentration (p=0.05) were significant predictors of severe OHSS. In both models, lack of fit was not significant. Tabled 1[hCG] IU/LEstimated prob(OHSS)Estimated prob(severe OHSS)Follicle countFollicle count15253545152535451000.2%1.6%11.5%50.5%0.1%0.7%4.3%22.6%2000.4%2.7%17.9%63.1%0.2%1.2%7.2%33.7%3000.6%4.5%26.8%74.2%0.3%2.0%11.8%46.9%4001.0%7.3%38.1%82.8%0.5%3.4%18.9%60.6% Open table in a new tab Conclusions: The hCG serum concentration has a dramatic effect on the probability of OHSS and severe OHSS. Patients with low follicle count have relatively low risk of OHSS regardless of hCG level. Clinicians should use restrained hCG dosage, particularly when 25 or more follicles are present.

Predictive value of serum oestradiol concentrations and oocyte number in severe ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of gonadotrophin usage but it is difficult to accurately predict its occurrence. Previous investigators have identified the combination of high oestradiol concentrations and oocyte number as being predictive in 80% of cases. In this study we sought to identify the incidence of severe OHSS in patients with high oestradiol concentrations and large numbers of oocytes and to evaluate the importance of pregnancy in the development of OHSS. Between 1990 and 1993, we studied 139 cycles using two assisted reproductive techniques [oocyte donor, n = 72; in-vitro fertilization (IVF), n = 67] in which either oestradiol (> 4000 pg/ml), oocyte number (> 25), or both were elevated. OHSS was diagnosed by standard criteria. There were no cases of severe OHSS in the oocyte donor group and six in the IVF group. Among 10 patients with oestradiol concentration > 6000 pg/ml and > 30 oocytes, only one had OHSS (10%). The relative risk of OHSS with pregnancy was 12 (confidence interval 2.18-66.14). We conclude that the risk of OHSS even at high levels of stimulation is lower than previously believed. Secondly, donors have a very low risk of OHSS, probably because of the absence of pregnancy. As such, cryopreservation of all oocytes in IVF cycles is a reasonable alternative to cycle cancellation or use of adjunctive medication.