We present a rare case of severe ovarian hyperstimulation syndrome (OHSS) in a 19-year-old woman undergoing a second donation cycle of controlled ovarian hyperstimulation. The patient developed severe OHSS despite the implementation of preventive strategies and required hospitalization for 14 days, including treatment in the intensive care unit. The underlying pathophysiology that triggers this extreme systemic response in certain patients, despite the implementation of preventive measures, remains unknown. Continued research efforts are necessary to improve our understanding and management of this condition.

OBJECTIVE: Does splitting the human chorionic gonadotrophin (HCG) support in IVF cycles triggered by a gonadotrophin-releasing hormone agonist result in a better progesterone profile?
METHODS: Randomized controlled three-arm study, performed at the Fertility Clinic, Odense University Hospital, Denmark. Patients with 12-25 follicles ≥12 mm were randomized into three groups: Group 1 - ovulation triggered with 6500 IU HCG; Group 2 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1500 IU HCG on the day of oocyte retrieval (OCR); and Group 3 - ovulation triggered with 0.5 mg GnRH agonist, followed by 1000 IU HCG on the day of OCR and 500 IU HCG on OCR + 5. All groups received 180 mg vaginal progesterone. Progesterone concentrations were analysed in eight blood samples from each patient.
RESULTS: Sixty-nine patients completed the study. Baseline and laboratory data were comparable. Progesterone concentration peaked on OCR + 4 in Groups 1 and 2, and peaked on OCR + 6 in Group 3. On OCR + 6, the progesterone concentration in Group 2 was significantly lower compared with Groups 1 and 3 (P = 0.003 and P < 0.001, respectively). On OCR + 8, the progesterone concentration in Group 3 was significantly higher compared with the other groups (both P<0.001). Progesterone concentrations were significantly higher in Group 3 from OCR + 6 until OCR + 14 compared with the other groups (all P ≤ 0.003). Four patients developed ovarian hyperstimulation syndrome in Group 3.
CONCLUSIONS: Sequential HCG support after a GnRH agonist trigger provides a better progesterone concentration in the luteal phase.

OBJECTIVE: What are the potential risk factors for poor oocyte recuperation rate (ORR) and oocyte immaturity after GnRH agonist (GnRHa) ovulation triggering?
CONCLUSIONS: Lower ovarian reserve and LH levels after GnRHa triggering are risk factors of poor ORR. Higher BMI and anti-Müllerian hormone (AMH) levels are risk factors of poor oocyte maturation rate (OMR).
BACKGROUND: The use of GnRHa to trigger ovulation is increasing. However, some patients may have a suboptimal response after GnRHa triggering. This suboptimal response can refer to any negative endpoint, such as suboptimal oocyte recovery, oocyte immaturity, or empty follicle syndrome. For some authors, a suboptimal response to GnRHa triggering refers to a suboptimal LH and/or progesterone level following triggering. Several studies have investigated a combination of demographic, clinical, and endocrine characteristics at different stages of the treatment process that may affect the efficacy of the GnRHa trigger and thus be involved in a poor endocrine response or efficiency but no consensus exists.
METHODS: Bicentric retrospective cohort study between 2015 and 2021 (N = 1747).
METHODS: All patients aged 18-43 years who underwent controlled ovarian hyperstimulation and ovulation triggering by GnRHa alone (triptorelin 0.2 mg) for ICSI or oocyte cryopreservation were included. The ORR was defined as the ratio of the total number of retrieved oocytes to the number of follicles >12 mm on the day of triggering. The OMR was defined as the ratio of the number of mature oocytes to the number of retrieved oocytes. A logistic regression model with a backward selection method was used for the analysis of risk factors. Odds ratios (OR) are displayed with their two-sided 95% confidence interval.
RESULTS: In the multivariate analysis, initial antral follicular count and LH level 12-h post-triggering were negatively associated with poor ORR (i.e. below the 10th percentile) (OR: 0.61 [95% CI: 0.42-0.88]; P = 0.008 and OR: 0.86 [95% CI: 0.76-0.97]; P = 0.02, respectively). A nonlinear relationship was found between LH level 12-h post-triggering and poor ORR, but no LH threshold was found. A total of 25.3% of patients suffered from oocyte immaturity (i.e. OMR < 75%). In the multivariate analysis, BMI and AMH levels were negatively associated with an OMR < 75% (OR: 4.34 [95% CI: 1.96-9.6]; P < 0.001 and OR: 1.22 [95% CI: 1.03-1.12]; P = 0.015, respectively). Antigonadotrophic pretreatment decreased the risk of OMR < 75% compared to no pretreatment (OR: 0.72 [95% CI: 0.57-0.91]; P = 0.02).
CONCLUSIONS: Our study is limited by its retrospective design and by the exclusion of patients who had hCG retriggers. However, this occurred in only six cycles. We were also not able to collect information on the duration of pretreatment and the duration of wash out period.
CONCLUSIONS: In clinical practice, to avoid poor ORR, GnRHa trigger alone should not be considered in patients with higher BMI and/or low ovarian reserve, balanced by the risk of ovarian hyperstimulation syndrome. In the case of a low 12-h post-triggering LH level, practicians must be aware of the risk of poor ORR, and hCG retriggering could be considered.
BACKGROUND: None.
BACKGROUND: N/A.

Is self-detection of the endogenous LH surge using a urine testing a reliable method to confirm a successful gonadotropin-releasing hormone agonist (GnRHa) trigger in IVF cycles?
Prospective observational study including a total of 103 oocyte donation cycles between November 2019 and January 2020. Urine LH testing (Akralab SL, Spain, cut-of value 30 mIU/mL) was performed at home in samples from the first micturition in the morning after the GnRHa trigger and a picture of the result was sent to the nurse coordinator; this information was concealed and only disclosed after oocyte aspiration.
From the total group, two cycles were excluded. A total of 101 oocyte donors performed the LH urine testing, all proceeded to oocyte aspiration and were included in final analysis. A total of 85 (84.2%) had a positive LH test and an uneventful oocyte retrieval with good retrieval rates (false positive rate: 0%). A total of 16 had a negative LH test (15.8%) and had a good oocyte retrieval rates (false negative rate: 15.8%). There were no cases of empty follicle syndrome.
Due to a high false negative rate, self-testing of endogenous LH release using a LH urine test when performed approximately 12-hours after triggering does not seem to be a reliable method to predict a suboptimal response to gonadotropin-releasing hormone.

The major limitations associated with gonadotropin-releasing hormone agonist (GnRHa) triggering are inferior clinical outcomes in fresh embryo transfer cycles caused by luteal phase insufficiency following the GnRHa triggering. We included 153 high-risk patients in this study. In group I, the patients received gonadotropin-releasing hormone agonist (GnRHa) trigger + 1,500 IU human chorionic gonadotropin (hCG) support on the oocyte pick-up (OPU) day; in group II, the patients had a dual trigger (GnRHa + 1,500 IU hCG); and in group III (control), 10,000 IU hCG trigger was prescribed for the final oocyte maturation. The levels of LH, estradiol, and progesterone were evaluated in serum on the stimulation starting day, day 6 of stimulation, on the day of the trigger administration, OPU day, days 3 and 5 post-OPU, and day 14 post-ET, as well as in follicular fluid. Progesterone concentration was significantly lower in group I on OPU+5 compared to the hCG group (I vs. III, р = 0.0065). Progesterone levels were significantly lower in group II in serum on OPU+5 compared to groups I and III (I vs. II, р = 0.0068; II vs. III, р = 1.76 × 108). The progesterone levels were significantly higher in follicular fluid in group III compared to the study groups (I vs. III, р = 0.002; II vs. III, p = 0.009). However, no significant differences in clinical outcomes were found between the groups. Then, we divided all women into pregnant and non-pregnant groups and found that estradiol (p = 0.00009) and progesterone (p = 0.000036) on the day of the pregnancy test were significantly higher in the pregnant women group. Also, progesterone on OPU day was significantly higher in the non-pregnant group (p = 0.033). Two cases of moderate ovarian hyperstimulation syndrome (OHSS) late-onset occurred in group I (3.5%, 2/56), no case of moderate/severe OHSS late-onset in group II, and three cases of moderate late-onset in group III (5.7%, 3/53). The low-dose hCG supplementation improves the luteal phase insufficiency after GnRHa triggering, which is confirmed by the comparable pregnancy rates in fresh transfer cycles between the groups. However, low-dose hCG carries a similar risk of OHSS as the full dose of hCG in high-responder patients.

Two modes of ovulation trigger are used in IVF: hCG, acting on ovarian LH receptors, and GnRH agonist, eliciting pituitary LH and FSH surges. These two modes are evaluated herein, focusing on how they serve specific time-sensitive events crucial for achieving embryo implantation and pregnancy. hCG trigger is associated with significant timing deviation from physiology. Peak progesterone is not synchronized with implantation window; progesterone level does not rise continuously to a mid-luteal peak, but rather drops from a too early peak. The luteal phase endocrinology post GnRH agonist trigger is characterized by a quick and irreversible luteolysis. Therefore, freeze all strategy is advised, if there is a risk of ovarian hyperstimulation syndrome. If fresh transfer is desired, numerous approaches for luteal phase support have been suggested. However, a thorough understanding of time-sensitive events suggests that a single 1,500 IU hCG dose, administered 48 h post oocyte retrieval, is all that is needed to fully support the luteal phase and secure best chances of achieving pregnancy.

OBJECTIVE: To evaluates the effect of different modes of final follicular maturation triggering on the degree of apoptosis of granulosa cells (GCs) and the potential effect on progesterone secretion.
METHODS: Thirty patients undergoing controlled ovarian hyperstimulation for IVF who received hCG, GnRH agonist, or dual trigger for final follicular maturation were included in the study. Granulosa cells were obtained at the time of oocyte retrieval. The proportion of apoptotic cells was evaluated via TUNEL and immunohistochemistry.
RESULTS: The proportion of apoptotic cells was significantly higher in the GnRH agonist-alone group compared to hCG-alone and the dual trigger groups (13.5 ± 1.5% vs. 7.8% ± 1.8 vs. 10.1% ± 2, respectively, P < 0.01). Moreover, the expression of active-caspase-3 was also significantly increased in the GnRH agonist-alone group compared with the hCG-alone and the dual trigger groups (15.5% ± 2.9 vs. 8.4% ± 1.6 vs. 12.7% ± 2.6, respectively, P < 0.01). The progesterone levels measured in the granulosa-luteal cell culture medium after 24 h of incubation were similar between the three groups.
CONCLUSIONS: The levels of apoptosis are increased after GnRH agonist/dual trigger. The increased apoptosis might be one of the culprit of the subsequent premature demise of the corpus luteum post GnRH agonist trigger.

Is the reproductive outcome similar after gonadotrophin-releasing hormone agonist (GnRHa) trigger followed by luteal human chorionic gonadotrophin (HCG) boluses compared with HCG trigger and a standard luteal phase support (LPS)?
Two open-label pilot randomized controlled trials (RCT) with 250 patients from 2014 to 2019, with a primary outcome of ongoing pregnancy per embryo transfer. Patients with ≤13 follicles on the trigger day were randomized (RCT 1) to: Group A (n = 65): GnRHa trigger followed by a bolus of 1500 IU HCG s.c. on the oocyte retrieval day (ORD) and 1000 IU HCG s.c. 4 days later, and no vaginal LPS; or Group B (n = 65): 6500 IU HCG trigger, followed by a standard vaginal progesterone LPS. Patients with 14-25 follicles on the trigger day were randomized (RCT 2) to Group C (n = 60): GnRHa trigger followed by 1000 IU HCG s.c. on ORD and 500 IU HCG s.c. 4 days later, and no vaginal LPS; or Group D (n = 60): 6500 IU HCG trigger and a standard vaginal LPS.
In RCT 1, the ongoing pregnancy rate was 44% (22/50) in the GnRHa group versus 46% (25/54) in the HCG trigger group (RR 0.95, 95% CI 0.62-1.45). No ovarian hyperstimulation syndrome (OHSS) was seen in Groups A or B. In RCT 2, the ongoing pregnancy rate was 51% (25/49) in the GnRHa group versus 60% (31/52) in the HCG trigger group (RR 0.86, 95% CI 0.60-1.22). The OHSS rates were 3.3% and 6.7%, respectively.
Although a larger-scale study is needed before standard clinical implementation, the present study supports that the exogenous progesterone-free LPS is efficacious, simple and patient-friendly.

The segmentation of the in vitro fertilization (IVF) cycle, consisting of the freezing of all embryos and the postponement of embryo transfer (ET), has become popular in recent years, with the main purpose of preventing ovarian hyperstimulation syndrome (OHSS) in patients with high response to controlled ovarian stimulation (COS). Indeed cycle segmentation (CS), especially when coupled to a GnRH-agonist trigger, was shown to reduce the incidence of OHSS in high-risk patients. However, CS increases the economic costs and the work amount for IVF laboratories. An alternative strategy is to perform a fresh ET in association with intensive luteal phase pharmacological support, able to overcome the negative effects of the GnRH-agonist trigger on the luteal phase and on endometrial receptivity. In order to compare these two strategies, we performed a retrospective, real-life cohort study including 240 non-polycystic ovarian syndrome (PCO) women with expected high responsiveness to COS (AMH >2.5 ng/mL), who received either fresh ET plus 100 IU daily human chorionic gonadotropin (hCG) as luteal support (FRESH group, n = 133), or cycle segmentation with freezing of all embryos and postponed ET (CS group, n = 107). The primary outcomes were: implantation rate (IR), live birth rate (LBR) after the first ET, and incidence of OHSS. Overall, significantly higher IR and LBR were observed in the CS group than in the FRESH group (42.9% vs. 27.8%, p < 0.05 and 32.7% vs. 19.5%, p < 0.05, respectively); the superiority of CS strategy was particularly evident when 16-19 oocytes were retrieved (LBR 42.2% vs. 9.5%, p = 0.01). Mild OHSS appeared with the same incidence in the two groups, whereas moderate and severe OHSS forms were observed only in the FRESH group (1.5% and 0.8%, respectively). In conclusion, in non-PCO women, high responders submitted to COS with the GnRH-antagonist protocol and GnRH-agonist trigger, CS strategy was associated with higher IR and LBR than the strategy including fresh ET followed by luteal phase support with a low daily hCG dose. CS appears to be advisable, especially when >15 oocytes are retrieved.

OBJECTIVE: Can the endometrial thickness (EMT) on the day of the LH surge predict pregnancy outcomes after single vitrified-warmed blastocyst transfers (SVBTs) in modified natural cycles?
UNASSIGNED: Decreased EMT on the day of the LH surge is associated with older female age and a shortened proliferation phase and may be associated with low live birth and high chemical pregnancy rates.
UNASSIGNED: The relation between EMT on the day of embryo transfer (ET) and pregnancy outcomes remains controversial; although numerous studies reported an association between decreased EMT on the day of ET and a reduced likelihood of pregnancy, recent studies demonstrated that the EMT on the day of ET had limited independent prognostic value for pregnancy outcomes after IVF. The relation between EMT on the day of the LH surge and pregnancy outcomes after SVBT in modified natural cycles is currently unknown.
UNASSIGNED: In total, 808 SVBTs in modified natural cycles, performed from November 2018 to October 2019, were analysed in this retrospective cohort study. Associations of EMT on the days of the LH surge with SVBT and clinical and ongoing pregnancy rates were statistically evaluated. Clinical and ongoing pregnancy rates were defined as the ultrasonographic observation of a gestational sac 3 weeks after SVBTs and the observation of a foetal heartbeat 5 weeks after SVBTs, respectively. Similarly, factors potentially associated with the EMT on day of the LH surge, such as patient and cycle characteristics, were investigated.
UNASSIGNED: The study includes IVF/ICSI patients aged 24-47 years, who underwent their first SVBT in the study period. After monitoring follicular development and serum hormone levels, ovulation was triggered via a nasal spray containing a GnRH agonist. After ovulation was confirmed, SVBTs were performed on Day 5. The EMT was evaluated by transvaginal ultrasonography on the day of the LH surge and immediately before the SVBT procedure.
UNASSIGNED: Of the original 901 patients, 93 who were outliers for FSH or proliferative phase duration data were excluded from the analysis. Patients were classified according to quartiles of EMT on day of the LH surge, as follows: EMT < 8.1 mm, 8.1 mm ≤ EMT < 9.1 mm, 9.1 mm ≤ EMT < 10.6 mm and EMT ≥ 10.6 mm. Decreased EMT on day of the LH surge was associated with lower live birth (P = 0.0016) and higher chemical pregnancy (P = 0.0011) rates. Similarly, patients were classified according to quartiles of EMT on day of the SVBT, as follows: EMT < 9.1 mm, 9.1 mm ≤ EMT < 10.1 mm, 10.1 mm ≤ EMT < 12.1 mm and EMT ≥ 12.1 mm. A decreased EMT on the day of SVBT was associated with a lower live birth rate (P = 0.0095) but not chemical pregnancy rate (P = 0.1640). Additionally, multivariate logistic regression analysis revealed a significant correlation between EMT on day of the LH surge and ongoing pregnancy; however, no correlation was observed between EMT on the day of SVBT and ongoing pregnancy (adjusted odds ratio 0.952; 95% CI, 0.850-1.066; P = 0.3981). A decreased EMT on day of the LH surge was significantly associated with greater female age (P = 0.0003) and a shortened follicular/proliferation phase (P < 0.0001).
UNASSIGNED: The data used in this study were obtained from a single-centre cohort; therefore, multi-centre studies are required to ascertain the generalisability of these findings to other clinics with different protocols and/or patient demographics.
UNASSIGNED: This is the first report demonstrating a significant correlation between EMT on day of the LH surge and pregnancy outcomes after frozen blastocyst transfer in modified natural cycles. Our results suggest that EMT on day of the LH surge may be an effective predictor of the live birth rate.
UNASSIGNED: This study was supported by resources from the Kato Ladies Clinic. The authors have no conflicts of interest to declare.