The good, the bad and the ugly of luteal phase stimulations.

An early follicular phase start of ovarian stimulation in assisted reproductive technology (ART) is only required if a fresh embryo transfer is planned. A shift from fresh to frozen embryo transfers has recently characterized ART treatments and, combined with the trend towards treatment individualization and simplification, facilitated random-start stimulation. Luteal phase stimulation, started between ovulation and the next menses, has gained momentum and the good, the bad and the ugly sides have become obvious with the increasing number performed. Unprotected intercourse during the follicular phase or around ovulation can result in an unknown and undetectable conception at the time of starting stimulation. Aside from the theoretical implications for embryo development from exposure to stimulation medication, embryo-derived human chorionic gonadotrophin may cause ovarian hyperstimulation syndrome. The duration of stimulation and consumption of gonadotrophin appear to be longer and higher than in the early follicular phase start approach, although the number of retrieved/mature oocytes is comparable or, in some instances, higher. On the other hand, elevated progesterone concentrations during the luteal phase may prevent premature ovulation and, in theory, might replace pituitary suppression using gonadotrophin-releasing hormone antagonists or exogeneous progestins. Furthermore, the flexibility in stimulation timing will meet the needs of patients with time constraints.

Severe ovarian hyperstimulation syndrome following sole gonadotropin-releasing hormone (GnRH) agonist trigger: a case series and literature review.

OBJECTIVE: The aim of this study was to report three cases of early severe ovarian hyperstimulation syndrome (OHSS) in patients undergoing a GnRH antagonist protocol triggered with GnRH agonist (GnRH-a), leading to hospitalization and the need for peritoneal drainage. Additionally, a review of the existing literature on this topic is provided. DESIGN: This is a retrospective case series and a literature review. SETTING: This study was conducted at obstetrics and gynecology department of tertiary academic referral hospitals, Israel. PARTICIPANTS: This study included three patients presented with severe OHSS symptoms, including abdominal distension, ascites, and hemoconcentration. MAIN OUTCOME MEASURES: The main focus of the treatment was to address the symptoms and prevent any further complications. The outcome was the complete recovery of the patients. RESULTS: The presented cases detail instances of severe OHSS following oocyte retrieval, utilizing GnRH-a for triggering. Case 1 involved a 33-year-old patient with a history of polycystic ovary syndrome (PCOS), Case 2 featured a 22-year-old patient with familial adenomatous polyposis (FAP), and Case 3 included a 41-year-old patient with a history of depressive disorder. All patients receiving supportive care, including infusions and medications, exhibited gradual improvement during hospitalization, with complete resolution observed during the 20-day post-hospitalization check-up. CONCLUSIONS: These three cases highlight the occurrence of severe early OHSS following a GnRH antagonist protocol triggered with GnRH-a in the absence of human chorionic gonadotropin (hCG) administration for trigger or luteal-phase support. Clinicians must be aware that a GnRH-a trigger followed by a freeze-all approach does not guarantee the complete elimination of OHSS in all patients.

Optimized personalized management approach for moderate/severe OHSS: development and prospective validation of an OHSS risk assessment index.

STUDY QUESTION: Can a simplified ovarian hyperstimulation syndrome (OHSS) risk assessment index be developed and validated with sufficient discrimination of moderate/severe OHSS from those without OHSS? SUMMARY ANSWER: This easy-to-use OHSS risk assessment index shows good discriminative power and high calibration accuracy in internal and external validation cohorts. WHAT IS KNOWN ALREADY: An early alert and risk stratification is critical to prevent the occurrence of OHSS. We have previously developed a multi-stage smartphone app-based prediction model to evaluate the risk of OHSS, but app use might not be so convenient in many primary institutions. A simplified OHSS risk assessment index has been required. STUDY DESIGN, SIZE, DURATION: This training and internal validation of an OHSS risk assessment index used retrospective cohort data from January 2016 to December 2020. External validation was performed with a prospective cohort database from January 2021 to May 2022. There were 15 066 cycles in the training cohort, 6502 cycles in the internal validation cohort, and 8097 cycles in the external validation cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed in the reproductive medicine center of a tertiary hospital. Infertile women who underwent ovarian stimulation were included. Data were extracted from the local database with detailed medical records. A multi-stage risk assessment index was constructed at multiple stages. The first stage was before the initiation of ovarian stimulation, the second was before the ovulation trigger, the third was after oocyte retrieval, and the last stage was on the embryo transfer day if fresh embryo transfer was scheduled. MAIN RESULTS AND THE ROLE OF CHANCE: We established a simplified multi-stage risk assessment index for moderate/severe OHSS, the performance of which was further evaluated with discrimination and calibration abilities in training and internal and external validation cohorts. The discrimination abilities of the OHSS risk assessment index were determined with C-statistics. C-statistics in training (Stages 1-4: 0.631, 0.692, 0.751, 0.788, respectively) and internal (Stages 1-4: 0.626, 0.642, 0.755, 0.771, respectively) and external validation (Stages 1-4: 0.668, 0.670, 0.754, 0.773, respectively) cohorts were all increased from Stage 1 to 3 with similar trends, and were comparable between Stages 3 and 4. Calibration plots showed high agreement between observed and predicted cases in all three cohorts. Incidences of OHSS based on diverse risk stratification (negligible risk, low risk, medium risk, and high risk) were 0%, 0.6%, 2.7%, and 8.3% in the training cohort, 0%, 0.6%, 3.3%, and 8.5% in the internal validation cohort, and 0.1%, 1.1%, 4.1%, and 7.2% in the external validation cohort. LIMITATIONS, REASONS FOR CAUTION: The influence from clinical interventions including cryopreservation of all embryos cannot be eliminated and thus certain risk factors like estrogen level on trigger day might be assigned with a lower risk score. Another weakness of the study is that several preventive treatments, for instance oral aspirin and letrozole, were not recorded and evaluated in the model. Despite the robust reliability of OHSS assessment index, this tool cannot be used directly for clinical decision-making or as a diagnostic tool. Its value lies in its capacity to evaluate the prognosis of various interventions and to facilitate clinician-patient communication. The combination of this tool and further symptoms and examinations should be all taken into consideration for accurate and personalized management of OHSS. WIDER IMPLICATIONS OF THE FINDINGS: The OHSS risk assessment index can be implemented to facilitate personalized counseling and management of OHSS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by National Key R&D Program of China (2022YFC2702504), Medical Research Fund Guangdong Provincial (A2024003), and Xinjiang Support Rural Science and Technology (Special Correspondent) Program in Guangdong Province (KTPYJ 2023014). All authors had nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

The best evidence for the management of ovarian hyper-stimulation syndrome in patients undergoing assisted reproductive therapy. / è¾ åŠ©ç”Ÿæ®–æ‚£è€ åµå·¢è¿‡åº¦åˆºæ¿€ç»¼åˆå¾ç®¡ç†çš„æœ€ä½³è¯æ®æ€»ç»“.

OBJECTIVES: To summarize the best evidence for the management of ovarian hyperstimulation syndrome in patients undergoing assisted reproductive therapy. METHODS: Evidence related to the management of ovarian hyperstimulation syndrome in patients undergoing assisted reproductive therapy, including practice guidelines, systematic evaluation, expert consensuws and evidence summary was systematically searched in UpToDate, BMJ Best Practice, World Health Organization (WHO) website, Guidelines International Network (GIN), National Institute for Health and Clinical Excellence (NICE) website, National Guidelines website, American Society for Reproductive Medicine (ASRM) website, New York Academy of Sciences (NYAS) website, Joanna Briggs Institute (JBI) database, Cochrane Library, CINAHL, PubMed, Wanfang Knowledge Data Service Platform, CNKI, and China Biomedical Literature Database from inception to March 1, 2024. Two researchers independently evaluated the quality of the literature, and a senior researcher made the final decision for literature inclusion. RESULTS: A total of 14 articles met the criteria, including 5 practical guidelines, 3 systematic evaluations, 2 expert consensuses, 1 evidence summary paper and 3 from UptoDate. The final formation includes five aspects: risk assessment, disease monitoring, early prevention, institutional management, and health education, with a total of 27 best pieces of evidence. CONCLUSIONS: The updated evidence indicates that the monitoring and prevention of ovarian hyperstimulation syndrome should start early; medical practitioners should provide personalized treatment plans for patients, promote the rational allocation of treatment resources, and enhance effective management of ovarian hyperstimulation syndrome.

Ischemic events are infrequent in patients with ovarian hyperstimulation syndrome.

BACKGROUND: Case reports describe arterial thrombosis including ischemic stroke associated with severe ovarian hyperstimulation syndrome (OHSS), but the prevalence of major ischemic events during or shortly after OHSS is unknown. METHODS: Using publicly available administrative datasets in the United States between 2015 and 2020, we conducted two separate cross-sectional studies of patients with OHSS. We included all patients with OHSS. Our study outcome was any hospitalization for acute ischemic stroke, acute myocardial infarction, cerebral venous sinus thrombosis, pulmonary embolism, or acute deep venous thrombosis during the index hospitalization or within 90 days of OHSS diagnosis. RESULTS AND CONCLUSIONS: We found very few major ischemic events in patients with OHSS.

Ovarian Hyperstimulation Syndrome (OHSS): A Narrative Review and Legal Implications.

BACKGROUND: Infertility is a highly meaningful issue with potentially life-changing consequences, and its incidence has been growing worldwide. Assisted reproductive technology (ART) has made giant strides in terms of treating many infertility conditions, despite the risk of developing ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication. METHODS: This narrative review draws upon scientific articles found in the PubMed database. The search spanned the 1990-2024 period. Search strings used included "OHSS" or "ovarian hyperstimulation" and "IVF" and "GnRH" and "hCG"; 1098 results were retrieved and were ultimately narrowed down to 111 suitable sources, i.e., relevant articles dealing with the condition's underlying dynamics, management pathways, and evidence-based criteria and guidelines, crucial both from a clinical perspective and from the standpoint of medicolegal tenability. RESULTS: The following features constitute OHSS risk factors: young age, low body weight, and polycystic ovarian syndrome (PCOS), among others. GnRH antagonist can substantially lower the risk of severe OHSS, compared to the long protocol with a gonadotropin-releasing hormone (GnRH) agonist. However, a mild or moderate form of OHSS is also possible if the antagonist protocol is used, especially when hCG is used for the final maturation of oocytes. For women at risk of OHSS, GnRH agonist trigger and the freeze-all strategy is advisable. OHSS is one of the most frequent complications, with a 30% rate in IVF cycles. CONCLUSION: Providing effective care for OHSS patients begins with early diagnosis, while also evaluating for comorbidities and complications. In addition to that, we should pay more attention to the psychological component of this complication and of infertility as a whole. Compliance with guidelines and evidence-based best practices is essential for medicolegal tenability.

The effect of intravenous calcium gluconate on the prevention of ovarian hyperstimulation syndrome. (A randomized clinical trial).

OBJECTIVE: Oral Cabergoline and intravenous Calcium have the potential to prevent Ovarian Hyperstimulation Syndrome (OHSS) in assisted reproductive technology by regulating the activity of the Vascular Endothelial Growth Factor (VEGF) receptor. The purpose of this study was to examine the effect of Cabergoline with intravenous Calcium versus oral Cabergoline alone on the overall rate of OHSS. METHODS: This study is a randomized clinical trial which was carried out in Milad Infertility Center affiliated with Mashhad University of Medical Sciences, Mashhad, Iran between April 2016 and January 2018. A total of 192 patients were randomly assigned into two groups. The control group received oral Cabergoline and the intervention group received Calcium gluconate in addition to Cabergoline. A total rate of OHSS, moderate and severe OHSS were measured in both groups. RESULTS: The demographic characteristics of the participants and the types of drugs used showed homogeneity between the intervention and control groups (P > 0.05). Furthermore, there was no significant difference between the two groups in terms of the number of the follicle, oocytes obtained, metaphase II oocytes, the number of embryos, and the rate of fertilization. Regarding the incidence of OHSS, 26.2 % of participants in the control group experienced OHSS, while the occurrence rate was 15.7 % in the intervention group (P = 0.401). The incidence of severe OHSS in the control group and intervention group was 7.1 % and 3.6 %, respectively. CONCLUSION: Intravenous injection of Calcium gluconate can be effective in preventing Ovarian Hyperstimulation Syndrome.

Extended versus conventional letrozole regimen in patients with polycystic ovary syndrome undergoing their first ovulation induction cycle: a prospective randomized controlled trial.

STUDY QUESTION: Can an extended letrozole (LE) regimen result in a higher ovulatory rate than a conventional regimen in patients with polycystic ovary syndrome (PCOS) undergoing their first ovulation induction cycle? SUMMARY ANSWER: There was no statistical difference in ovulation rate between patients with PCOS using the extended LE regimen and those using the conventional LE regimen. WHAT IS KNOWN ALREADY: LE has become the first-line agent for ovulation induction. However, there is still a proportion of non-responsive cycles in patients with PCOS undergoing ovulation induction therapy with LE alone, and the extended LE regimen has been demonstrated to be a feasible method for inducing ovulation in these non-responders. Nevertheless, whether the extended regimen could be applied to all patients with PCOS as a first choice for the induction of ovulation remains to be explored. STUDY DESIGN SIZE DURATION: This was a prospective randomized controlled trial that included 148 female patients with PCOS who underwent their first ovulation induction cycle with LE from January 2021 to October 2022. PARTICIPANTS/MATERIALS SETTING METHODS: Participants were randomly assigned to receive an extended (5 mg LE daily for 7 days) or conventional regimen (5 mg LE daily for 5 days) for one treatment cycle. The ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, and the rate of multiple pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE: The ovulation rate among patients receiving an extended LE regimen was slightly higher than the rate with a conventional LE regimen, but the difference did not reach statistical significance in either the intention-to-treat analysis (90.54% [67/74] vs 79.73% [59/74], P = 0.065; relative risk [95% CI]: 0.881 [0.768-1.009]) or the per-protocol analysis (90.54% [67/74] vs 84.29% [59/70], P = 0.257; relative risk [95% CI]: 0.931 [0.821-1.055]). The number of preovulatory follicles was nearly identical in the two groups (1.39 ± 0.62 vs 1.37 ± 0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. With regards to the endometrial parameters, the mean endometrium thickness was slightly thicker with the conventional LE regimen compared to that with the extended LE regimen, though with no statistical difference (9.27 ± 1.72 mm vs 9.57 ± 2.28 mm, P = 0.792). In the per-protocol analysis, the rates of clinical pregnancy (20.27% [15/74] vs 14.29% [10/70], P = 0.343; relative risk [95% CI]: 0.705 [0.34-1.463]) and live birth (13.51% [10/74] vs 11.43% [8/70], P = 0.705; relative risk [95% CI]: 0.846 [0.354-2.019]) did not differ significantly between treatment groups. Moreover, all conceptions were singletons without neonatal defects. LIMITATIONS REASONS FOR CAUTION: The major concerns regarding this study are its single-center and open-label nature. Additionally, the limited number of lean patients with PCOS with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restricted the generalizability of our findings. WIDER IMPLICATION OF THE FINDINGS: A change from the standard strategy of ovulation induction in patients with PCOS is not advisable, because a statistically superior effect of the extended LE regimen over a conventional regimen was not detected. The extended LE regimen could be applied with caution in a specific population who failed to respond to a conventional regimen rather than all the patients with PCOS during ovulation induction. Additional prospective trials with larger sample sizes and different PCOS subgroups are needed to assess the ovulatory effects of various LE treatment durations. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Shanghai First Maternity and Infant Hospital, affiliated with Tongji University School of Medicine (grant numbers: 2023B03 to Y.F., 2023B18 to X.Z., and 2020RC02 to Y.F.). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2100042082). TRIAL REGISTRATION DATE: 13 January 2021. DATE OF FIRST PATIENT'S ENROLMENT: 21 January 2021.

The Effect of Progesterone Elevation on the Day of Trigger Administration: A Review of the Literature.

Since the advent of assisted reproductive technology, different variables have been shown to affect pregnancy outcomes. One of the most prevalent studied events is the premature rise in serum progesterone concentrations on the day of trigger administration during cycles of ovarian stimulation. This phenomenon, classically known as premature luteinization, has been observed significantly for decades and has been linked to adverse pregnancy outcomes and lower live birth rates. Ultimately, a quest to find a precise serum progesterone concentration cut-off value that can be effectively used to predict pregnancy outcomes prior to trigger administration is still underway. The purpose of the current research was to study the available literature on the relationship between serum progesterone on the day of trigger administration in controlled ovarian stimulation cycles used for IVF in an attempt to identify a cut-off serum progesterone concentration that can be used to effectively predict future pregnancy outcomes in fresh transfers. This study is a review of the literature and is based on information and data gathered from 36 published articles. The majority of the literature shows that a serum progesterone concentration cut-off of 1.5 ng/ml (4.77 nmol/L) can be used prior to trigger administration to effectively predict pregnancy outcomes. Premature progesterone elevation on the day or prior to the trigger administration is associated with adverse pregnancy outcomes in IVF cycles. Other factors such as follicle number, serum concentration of other hormones, and ovarian response to ovarian stimulation should also be considered to predict the success of IVF protocols.

Effect of aromatase inhibitors for preventing ovarian hyperstimulation syndrome in infertile patients undergoing in vitro fertilization: a systematic review and meta-analysis.

PURPOSE: To summarize the findings of relevant randomized controlled trials (RCTs) and conduct a meta-analysis to investigate the potential effect of aromatase inhibitors on preventing moderate to severe ovarian hyperstimulation syndrome (OHSS) in infertile women undergoing in vitro fertilization (IVF). METHODS: We searched for relevant RCTs in electronic databases, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (from inception to August 2023). In addition, we manually searched the related reviews and reference lists of included studies for further relevant studies. We included RCTs where aromatase inhibitors prescribed either during controlled ovarian stimulation (COS) or in early luteal phase. The meta-analysis was performed using RevMan 5.4.1 software. The primary outcome was the incidence of moderate to severe OHSS. A descriptive analysis was conducted in cases where a meta-analysis was not feasible due to heterogeneity or lack of comparable data. RESULTS: 2858 records were retrieved and 12 RCTs were finally included. Letrozole was administered in the treatment group during COS in seven RCTs, whereas in the early luteal phase in five RCTs. Compared with the control group, the risk of moderate to severe OHSS significantly reduced by 55% in the letrozole group (RR 0.45, 95% CI 0.32 to 0.64, I2 = 0%, 5 RCTs, 494 patients). Moreover, serum estradiol (E2) levels on hCG trigger day significantly decreased with the administration of letrozole during COS (MD -847.23, 95% CI -1398.00 to -296.47, I2 = 93%, 5 RCTs, 374 patients). And serum E2 levels on the 4th, 5th and 7th to 10th day after hCG trigger were also significantly lower than those in the control group when letrozole was administered in the early luteal phase. CONCLUSIONS: Patients with high risk of OHSS probably benefit from letrozole, which has been revealed to reduce the incidence of moderate to severe OHSS by this systematic review. However, the very limited number of participants and the quality of the included studies does not allow to recommend letrozole for the prevention of severe OHSS.

Melatonin improves fertilization rate in assisted reproduction: Systematic review and meta-analysis.

BACKGROUND: Melatonin is a hormone produced by the pineal gland and it has antioxidant properties. AIM: This study aimed to evaluate the effects of melatonin on assisted reproductive technologies through a systematic review and a meta-analysis. MATERIALS AND METHODS: Search strategies were used in PubMed and in other databases covering the last 15 years. After screening for eligibility, 17 articles were selected for the systematic review. For the meta-analysis statistics, two groups were formed, the treatment group (with melatonin) and the control group (without melatonin) for various assisted reproduction outcomes. RESULTS: The main results were that no statistical differences were found concerning the clinical pregnancy outcome (p = 0.64), but there was a statistical difference with respect to Mature Oocytes (MII) (p = 0.001), antral follicle count (p = 0.0002), and the fertilization rate (p ≤ 0.0001). CONCLUSIONS: Melatonin had beneficial effects such as the improvement in the fertilization rate, although the authors did not obtain significance in the clinical pregnancy rate.

Calcium versus cabergoline for prevention of ovarian hyperstimulation syndrome: A systematic review and meta-analysis.

AIM: To conduct the first-ever systematic review and meta-analysis evaluating calcium infusion versus cabergoline in preventing ovarian hyperstimulation syndrome (OHSS) among high-risk women undergoing assisted reproductive technology. METHODS: Six databases were screened from inception until April 1, 2024. The included randomized and non-randomized controlled studies were assessed for quality. The endpoints included the severity of OHSS and selected pregnancy-related outcomes. Endpoints were summarized as risk ratios (RRs) and 95% confidence intervals (CIs) in a random-effects model. RESULTS: Six studies were analyzed, including 1687 patients (828 in the calcium group and 859 in the cabergoline group). The quality of the studies varied and reflected low risk and high risk of bias in two and four studies, respectively, according to the revised Cochrane risk of bias tool. No significant differences were noted between both groups regarding the rates of overall (n = 5, RR = 0.65, 95 % CI [0.39, 1.07], p = 0.09), mild (n = 4, RR = 1.05, 95 % CI [0.59, 1.89], p = 0.86), moderate (n = 5, RR = 0.41, 95 % CI [0.15, 1.08], p = 0.07), and severe (n = 6, RR = 0.36, 95 % CI [0.11, 1.22], p = 0.1) cases of OHSS. Leave-one-out sensitivity analysis of an outlier study revealed that calcium significantly reduced the occurrence of severe OHSS compared with cabergoline (n = 5, RR = 0.16, 95 % CI [0.09, 0.43], p < 0.001, Higgins I2 = 0 %). No significant differences were observed between both groups regarding the rates of clinical pregnancy (n = 4, RR = 0.97, 95 % CI [0.88, 1.07], p = 0.57), ongoing pregnancy, live birth, and spontaneous abortion (Higgins I2 < 50 % for all). CONCLUSION: Both agents yielded similar pregnancy-related outcomes. However, calcium infusion could potentially be more effective than cabergoline in reducing the rate of severe OHSS. Additional high-quality and well-controlled trials are essential to draw firm conclusions.

Undetected, natural conception pregnancies in luteal phase stimulations-case series and review of literature.

STUDY QUESTION: What is the risk of an undetected natural conception pregnancy during luteal phase ovarian stimulation, and how does it impact the pregnancy's course? SUMMARY ANSWER: The risk for an undetected, natural conception pregnancy in luteal phase ovarian stimulation is low and it appears that ovarian stimulation is unlikely to harm the pregnancy. WHAT IS KNOWN ALREADY: Random start ovarian stimulation appears to be similarly effective as early follicular stimulation start; and it allows ovarian stimulation to be started independent of the cycle day and throughout the cycle, in accordance with the patients' and clinics' schedule as long as there is no intention of a fresh embryo transfer in the same cycle. Starting ovarian stimulation in the luteal phase bears the possibility of an-at the timepoint of stimulation start-undetected, natural conception pregnancy that has already occurred. There is scarce data on the incidence of this event as well as on the possible implications of ovarian stimulation on the course of an existing pregnancy. STUDY DESIGN, SIZE, DURATION: This retrospective observational study, performed between June 2017 and January 2024, analyzed luteal phase stimulations, in which a natural conception pregnancy was detected during the ovarian stimulation treatment for IVF/ICSI. Luteal phase stimulation was defined as ovarian stimulation started after ovulation and before the next expected menstrual bleeding, with a serum progesterone (P4) level of >1.5 ng/ml on the day of stimulation start or 1 day before. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who underwent a luteal phase ovarian stimulation in a tertiary referral ART center. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 488 luteal phase stimulation cycles were included in the analysis. Luteal phase stimulation was only started after a negative serum hCG measurement on the day or 1 day before commencement of ovarian stimulation. Ten patients (2.1%) had an undetected natural conception pregnancy at the time of luteal phase stimulation start. Eight of these patients underwent an ovarian stimulation in a GnRH-antagonist protocol and two in a progestin-primed stimulation protocol (PPOS). Recombinant FSH was used as stimulation medication for all patients, the patients with a PPOS protocol received additional recombinant LH. One pregnancy (0.2%) was detected after the oocyte retrieval, the other nine pregnancies were detected either due to persistent high serum progesterone levels or due to an increasing progesterone level after an initial decrease before oocyte retrieval. In the cycles with an undetected natural conception pregnancy, the median number of stimulation days was 8 days (range: 6-11 days) and median serum hCG at detection of pregnancy was 59 IU hCG (range: 14.91-183.1). From 10 patients with a pregnancy, three patients delivered a healthy baby, two patients had ongoing pregnancies at the time of summarizing the data, three patients had biochemical pregnancies (patient age: 30, 39, and 42 years), one patient had an ectopic pregnancy which required a salpingectomy, and one patient (age: 34 years) had an early pregnancy loss. LIMITATIONS, REASONS FOR CAUTION: The retrospective study design and the small sample size can limit the accuracy of the estimates. WIDER IMPLICATIONS OF THE FINDINGS: Overall, there is a small risk of undetected natural conception pregnancies when luteal phase stimulation is undertaken. It appears that there are no adverse effects through either direct effect on the embryo or indirectly through a detrimental effect on the corpus luteum function on the pregnancy in our cohort. STUDY FUNDING/COMPETING INTEREST(S): This study did not receive funding. The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Severe ovarian hyperstimulation syndrome in an oocyte donor despite preventive strategies.

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.

Fertility Preservation and Ovarian Hyperstimulation Syndrome Management in Cancer Care: A Pathophysiological Perspective on Gonadotropin-Releasing Hormone Agonists and Antagonists.

This narrative review delves into the evolving landscape of fertility preservation techniques, with a particular focus on their use in patients undergoing oncology treatment that carries a risk of ovarian insufficiency. Advances in established methods such as cryopreservation of oocytes and embryos are highlighted, and the increasing use of gonadotropin-releasing hormone (GnRH) agonists is discussed. The review also addresses the complexities and controversies associated with these approaches, such as the 'flare-up' effect associated with GnRH agonists and the potential of GnRH antagonists to reduce the risk of ovarian hyperstimulation syndrome. Despite advances in fertility preservation, the report highlights the challenges we face, including the need for personalized treatment protocols and the management of associated risks. It calls for continued research and collaboration between healthcare professionals to refine these techniques and ultimately improve reproductive outcomes for patients facing the prospect of fertility-impairing treatment.

Betaine Attenuates The Expression of Vasoactive Mediators and Histological Alterations Associated with Ovarian Hyperstimulation Syndrome in Rats.

OBJECTIVE: Ovarian hyperstimulation syndrome (OHSS) is one female reproductive disorder that can occur after administration of injectable hormonal drugs to stimulate ovulation. Betaine (BET) is an intracellular biomolecule with anti-inflammatory and tissue protective effects. There is no information about its effects in an experimental model of OHSS. The current study aims to investigate the possible effects of BET on abnormal expressions of vasoconstrictor proteins and ovarian histological changes in an experimental OHSS rat model. MATERIALS AND METHODS: In this experimental study, 30 adult female rats (two months old) were randomly divided into six groups (n=5 per group): i. Control, ii. OHSS [10 IU sc equine chorionic gonadotropin (eCG) for 4 days followed by 30 IU sc human chorionic gonadotropin (hCG) on the fifth day], iii. OHSS+BET (200 mg/kg/day, orally for seven days), iv. OHSS+Cabergoline (CAB, 100 mg/kg/day, orally for six days), v. BET, and vi. CAB. Expression levels of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and blood levels of oestradiol (E2) and progesterone (P4) were measured at the end of the experiment. The ovaries were studied for histomorphological changes. RESULTS: Induction of OHSS altered tissue histology, including an increase in the number of corpora lutea and atretic follicles, and decreased the number of follicular reserves. In this group, we observed increased expressions of the VEGF and COX-2 proteins, and increased serum E2 and P4 levels. Administration of CAB and BET significantly attenuated all molecular and histological alterations observed in the OHSS animals. CONCLUSION: Our findings, for first time, indicate the beneficial effects of BET to reduce OHSS complications in patients by reducing the expressions of vasoactive proteins and improving changes to the ovarian tissues. The findings are similar to CAB and can be a new avenue for future research on BET.

Ovarian Hyperstimulation syndrome combined with hypothyroidism: a comprehensive review.

Ovarian Hyperstimulation Syndrome (OHSS) is a systemic condition marked by the enlargement of the ovaries and heightened vascular permeability. And hypothyroidism (HT) emerges as a potential risk factor for OHSS occurrence. This review presented a comprehensive summary of pertinent case reports involving patients diagnosed with both HT and OHSS. Detailed exploration was conducted into their clinical presentations, diagnostic methodologies, and treatment modalities. Additionally, the review delved into potential interaction mechanisms between HT and OHSS, encompassing various aspects including hormone levels. Moreover, management strategies for mitigating the risk of OHSS in HT patients were thoroughly reviewed and the importance of monitoring thyroid function in those experiencing OHSS was emphasized. This review indicated that the association between HT and OHSS, underscoring its multifaceted complexity. It could accentuate the ongoing necessity for rigorous research and clinical refinement to deepen our comprehension of this association and to bolster diagnostic and therapeutic methodologies for optimal patient care. In conclusion, this review offered valuable insights for future research directions and clinical practices for patients afflicted with OHSS and HT.

Individualized dosing of follitropin delta affects live birth and safety in in vitro fertilization treatment: an individual participant data meta-analysis of randomized controlled trials.

OBJECTIVE: To undertake a one-stage meta-analysis of individual patient data from randomized trials comparing individualized dosing of follitropin delta vs. other forms of follitropin (alpha and beta) for live birth (LB) rates (LBR) and safety parameters in women undergoing ovarian stimulation for in vitro fertilization treatment. DESIGN: Systematic review with individual patient data meta-analysis. SETTING: Not applicable. PATIENTS: Women undergoing ovarian stimulation for in vitro fertilization treatment. INTERVENTIONS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Web of Science to identify eligible phase 3 trials between January 1, 2000, and February 1, 2023. MAIN OUTCOME MEASURES: All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drugs interacting with log (AMH) level, age, and random effects for country and trial to compare the primary efficacy and safety outcomes of LB and early ovarian hyperstimulation syndrome (OHSS) and/or the need for OHSS preventative measures, with ovarian stimulation parameters and neonatal outcomes also assessed. PROSPERO registration: CRD42023399711. RESULTS: Three trials met inclusion criteria and included 2,685 women undertaking 2,682 cycles between October 2013 and May 2020, with LB follow-up through to February 1, 2023. For women with an elevated AMH level (≥15 pmol/L), there was high-quality evidence that the use of individualized dosing of follitropin delta was associated with an increased LB rate (adjusted odds ratio [adj OR] 1.64, 95% confidence interval [CI] 1.14, 2.36). Safety outcomes were also improved with a reduced risk of both early OHSS and/or the need for preventative interventions (adj OR 0.27, 95% CI 0.15, 0.49) and early moderate or severe OHSS (adj OR 0.30, 95% CI 0.16, 0.58). These improvements in outcomes were obtained with a lower total dose of gonadotropin (-48.7 µg, 95% CI -53.7, -43.8) and no adjustments in the daily dose. In contrast, similar LB rates (adj OR 0.86, 95% CI 0.63, 1.17) and safety outcomes (adj OR 1.92, 95% CI 0.76, 4.87) were observed for women with an AMH level of <15 pmol/L. There were no clinically meaningful differences in neonatal outcomes. CONCLUSION: Using follitropin delta in an AMH level and weight-based algorithm rather than conventional licensed dosing of follitropin alpha or beta for ovarian stimulation in women is associated with improved LB rates and safety outcomes for women with elevated AMH levels.

Efficacy of Dan'e Fukang Soft Extract in Moderate Ovarian Hyperstimulation Syndrome for Concurrent Treatment of Blood and Fluid Guided by the "Triple Prevention" Principle.

Objective: This study aimed to evaluate the therapeutic efficacy and safety of Dan'e Fukang soft extracts in moderate ovarian hyperstimulation syndrome (OHSS) for the simultaneous treatment of blood and fluid, guided by the traditional Chinese medicine principle of "triple prevention". Methods: This study conducted a retrospective analysis of clinical data from outpatients who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection embryo transfer (ICSI-ET). A total of 2245 cases were included and divided into a treatment group (1002 cases) and a control group (1243 cases). Patients in the treatment group were administered Dan'e Fukang soft extracts orally in addition to conventional Western medicine. Comparative assessments were made between the two groups on pelvic ascites volume, maximum ovary diameter, dysmenorrhea incidence post-oocyte retrieval, and safety indicators. Results: There were no statistically significant differences between the treatment group and the control group in terms of general characteristics or the levels of follicle-stimulating hormone (FSH), luteotropic hormone (LH), estradiol (E2), or progesterone (P) at the time of gonadotropin (Gn) initiation. The groups did not differ significantly when we compared the levels of LH, E2, or P on the day of human chorionic gonadotropin (hCG) injection and during ovarian hyperstimulation protocols (P > 0.05 for all indicators). The differences in the volume of pelvic ascites, the maximum ovarian diameter, and the incidence of dysmenorrhea after oocyte retrieval were statistically significant between the treatment group and the control group (P < 0.05 in both). There were no instances of adverse reactions in either group. Conclusion: Based on the traditional Chinese medicine principle of "triple prevention", the use of Dan'e Fukang soft extracts for the simultaneous treatment of blood and fluid in moderate OHSS significantly improved the absorption of pelvic ascites, promoted ovarian recovery, and reduced the incidence of dysmenorrhea after oocyte retrieval.

Efficacy and safety of follitropin delta versus follitropin alpha/beta in infertility treatment: A systematic review and meta-analysis.

Background: Follitropin δ may be an alternative to conventional follitropin α/ß for controlled ovarian stimulation (COS) within assisted reproductive treatment (ART), but its efficacy and safety remain unknown. We performed a random-effects meta-analysis to compare the efficacy and safety of follitropin δ and follitropin α/ß. Methods: We searched randomized controlled trials comparing follitropin δ and follitropin α/ß using MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO-ITCRP on December 14, 2022. The primary outcomes were the live birth rate and the incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS). The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation approach. The protocol was registered on the Open Science Framework. Results: Three studies involving 2682 participants were included in our meta-analysis. The results indicated that follitropin δ may result in little to no difference in live birth rates (risk ratio [RR], 1.12; 95% confidence interval [CI], 0.91-1.38; low certainty) and the incidence of moderate or severe OHSS (RR, 0.78; 95% CI, 0.48-1.26; low certainty) compared with follitropin α/ß. Conclusion: Follitropin δ may result in little to no difference in COS compared with follitropin α/ß, especially in terms of live births and safety.