Comparison of Cumulative Live Birth Rates Between Progestin and GnRH Analogues in Preimplantation Genetic Testing Cycles.

CONTEXT: Progestins have recently been used as an alternative for gonadotropin-releasing hormone (GnRH) analogues to prevent premature luteinizing hormone surge due to the application of vitrification technology. However, the long-term efficacy and safety of a progestin-primed ovarian stimulation (PPOS) regimen, including oocyte competence, cumulative live birth rate (LBR), and offspring outcomes, remain to be investigated. OBJECTIVE: To compare cumulative LBR of preimplantation genetic testing (PGT) cycles between a PPOS regimen and GnRH analogues. METHODS: This was a retrospective cohort study at a tertiary academic medical center. A total of 967 patients with good prognosis were categorized into 3 groups, of which 478 patients received a long GnRH agonist, 248 patients received a GnRH antagonist, and 250 received a PPOS regimen. Medroxyprogesterone 17-acetate was the only progestin used in the PPOS regimen. The primary outcome was cumulative LBR. Secondary outcomes included time to live birth, cumulative rates of biochemical and clinical pregnancy and pregnancy loss, and perinatal outcomes. RESULTS: The PPOS regimen was negatively associated with cumulative LBR compared with GnRH antagonists and GnRH agonists (28.4% vs 40.7% and 42.7%). The average time to live birth was significantly shorter with GnRH antagonists than with the PPOS regimen. The cumulative biochemical and clinical pregnancy rates were also lower in the PPOS regimen than GnRH analogues, while cumulative pregnancy loss rates were similar across groups. Furthermore, the number and ratio of good-quality blastocysts were significantly reduced in the PPOS regimen compared with GnRH analogues. In addition, perinatal outcomes were comparable across 3 groups. CONCLUSION: A PPOS regimen may be adversely affect cumulative LBR and blastocyst quality in women with good prognosis compared with GnRH analogues in PGT cycles.

Association between serum LH levels on hCG trigger day and live birth rate after fresh embryo transfer with GnRH antagonist regimen in different populations.

Objective: To investigate whether serum LH levels on hCG trigger day are associated with live birth rate (LBR) after fresh embryo transfer with GnRH antagonist regimen in different populations. Methods: This study was a retrospective study. A total of 3059 fresh embryo transfers were divided into three populations: predicted normal ovarian responders (NOR) (n=2049), patients with PCOS (n=533), and predicted poor ovarian responders (POR) (n=477). Each population was stratified into three groups based on LH levels: < 25th percentile, 25-75th percentile, and > 75th percentile. The primary outcome of the study was LBR, and secondary outcomes included implantation, clinical pregnancy, and early pregnancy loss rates. Univariable and multivariable regression analyses were performed to adjust for potential confounders. Results: In NOR, compared to the reference group (>75th percentile), LBR was significantly lower in the < 25th percentile group (adjusted OR=0.662; 95%CI, 0.508-0.863) and 25-75th percentile group (adjusted OR=0.791; 95%CI, 0.633-0.988). In PCOS patients, LBR decreased significantly in the < 25th percentile group (41.4%) compared to the 25-75th percentile group (53.7%) and > 75th percentile group (56.1%). In addition, the LBR was lower in the < 25th percentile group (33.6%) compared with the 25-75th percentile group (43.4%) and the>75th percentile group (42.0%) in POR, but this was not statistically significant. Conclusions: High serum LH levels are associated with increased LBR after fresh embryo transfer in GnRH antagonist cycles, which may be attributable to higher implantation rate. LH may be a predictor of whether to schedule fresh embryo transfer in IVF cycles for better clinical outcomes.

Comparison of cumulative live birth rates between progestin-primed ovarian stimulation protocol and gonadotropin-releasing hormone antagonist protocol in different populations.

Objective: To compare cumulative live birth rate (LBR) between progestin-primed ovarian stimulation (PPOS) and GnRH antagonist protocols of preimplantation genetic testing (PGT) cycles in different populations. Methods: This was a retrospective cohort study. A total of 865 patients were enrolled and separate analyses were performed for three populations: 498 patients with predicted normal ovarian response (NOR), 285 patients with PCOS, and 82 patients with predicted poor ovarian response (POR). The primary outcome was cumulative LBR for one oocyte retrieval cycle. The results of response to ovarian stimulation were also investigated, including numbers of oocytes retrieved, MII oocytes, 2PN, blastocysts, good-quality blastocysts, and usable blastocysts after biopsy, as well as rates of oocyte yield, blastocyst formation, good-quality blastocysts, and moderate or severe OHSS. Univariable and multivariable logistic regression analyses were used to identify potential confounders that may be independently associated with cumulative live birth. Results: In NOR, the cumulative LBR of PPOS protocol was significantly lower than that of GnRH antagonists (28.4% vs. 40.7%; P=0.004). In multivariable analysis, the PPOS protocol was negatively associated with cumulative LBR (adjusted OR=0.556; 95% CI, 0.377-0.822) compared to GnRH antagonists after adjusting for potential confounders. The number and ratio of good-quality blastocysts were significantly reduced in PPOS protocol compared to GnRH antagonists (2.82 ± 2.83 vs. 3.20 ± 2.79; P=0.032 and 63.9% vs. 68.5%; P=0.021), while numbers of oocytes, MII oocytes and 2PN did not show any significant difference between GnRH antagonist and PPOS protocols. PCOS patients had similar outcomes as NOR. The cumulative LBR of PPOS group appeared to be lower than that of GnRH antagonists (37.4% vs. 46.1%; P=0.151), but not significantly. Meanwhile, the proportion of good-quality blastocysts in PPOS protocol was also lower compared to GnRH antagonists (63.5% vs. 68.9%; P=0.014). In patients with POR, the cumulative LBR of PPOS protocol was comparable to that of GnRH antagonists (19.2% vs. 16.7%; P=0.772). There was no statistical difference in the number and rate of good-quality blastocysts between the two protocols in POR, while the proportion of good-quality blastocysts appeared to be higher in PPOS group compared to GnRH antagonists (66.7% vs. 56.3%; P=0.182). In addition, the number of usable blastocysts after biopsy was comparable between the two protocols in three populations. Conclusion: The cumulative LBR of PPOS protocol in PGT cycles is lower than that of GnRH antagonists in NOR. In patients with PCOS, the cumulative LBR of PPOS protocol appears to be lower than that of GnRH antagonists, albeit lacking statistical difference, whereas in patients with diminished ovarian reserve, the two protocols were comparable. Our findings suggest the need for caution when choosing PPOS protocol to achieve live births, especially for normal and high ovarian responders.

Folic Acid Preconditioning Alleviated Radiation-Induced Ovarian Dysfunction in Female Mice.

Radiological therapy/examination is the primary source of artificial radiation exposure in humans. While its application has contributed to major advances in disease diagnosis and treatment, ionizing radiation exposure is associated with ovarian damage. The use of natural products, either alone or as an adjunct, has become increasingly common for reducing the side effects of radiological therapy during disease treatment. Herein, we explored the protective effect of folic acid (FA), a widely used B vitamin, against radiation-induced ovarian injury and its mechanism of action. Female mice with normal ovarian function were randomly divided into control, FA, radiation, and radiation + FA groups. The intervention strategy included daily intragastric administration of FA (5 mg/kg) for 3 weeks prior to radiation exposure. Mice in the radiation and radiation + FA groups received a single dose of 5 Gy X-ray irradiation. Changes in the estrous cycle were then recorded, and ovarian tissues were collected. Pathophysiological changes as well as reproductive and endocrine-related indexes were determined via H&E staining, immunohistochemistry, Western blot, and ELISA. The reproductive performance and emotional symptoms of animals were also monitored. Our results indicated that FA intervention effectively alleviated ovarian damage, leading to more regular estrous cycles, lesser impairment of follicular morphology and endocrine status, as well as greater germ cell preservation. Reduced levels of oxidative stress, inflammation, and enhanced DNA repair were associated these changes. FA pre-administration improved the reproductive performance, leading to higher pregnancy rates and greater litter sizes. Further, the anxiety levels of animals were significantly reduced. Our results indicate that FA pre-administration significantly alleviates radiation-induced ovarian damage in rodents, highlighting its potential as a protective strategy against radiation exposure in the female population.

The impact of different cycle regimens on birthweight of singletons in frozen-thawed embryo transfer cycles of ovulatory women.

OBJECTIVE: To investigate whether different endometrial preparation regimens affect neonatal outcomes after frozen-thawed embryo transfer (FET). DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: A total of 3,639 patients with live-born singletons were categorized into three groups on the basis of the type of endometrial preparation regimens. Of these, 1,225, 2,136, and 278 live-born singletons were conceived through natural cycle FET, artificial cycle FET, and stimulated cycle FET, respectively. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The main outcomes were the measures of birthweight including the absolute mean birthweight, Z-score, low birthweight, high birthweight (HBW), small for gestational age, and large for gestational age (LGA). RESULTS: After controlling for a variety of covariates, singletons from the artificial cycle FET group had a higher mean birthweight and Z-score than those from the natural cycle FET group and stimulated cycle FET group. The risk of LGA infants significantly increased in the artificial cycle group (14.0%) than that in the natural cycle group (10.3%) and stimulated cycle group (7.6%). The risk of hypertensive disorders of pregnancy in the artificial cycle group (4.4%) was significantly higher than that in the natural cycle group (2.5%). The stimulated cycle FET singletons had a higher risk of low birthweight than the natural cycle FET singletons. The other perinatal outcomes, including the incidence of preterm birth, small for gestational age, and gestational diabetes mellitus, were comparable between the groups before or after adjustment for confounders. CONCLUSIONS: Singletons from artificial cycle FET were associated with a higher risk of LGA infants, and natural cycle FET may be a better regimen for ovulatory women. Our results indicate a link between the absence of the corpus luteum and adverse perinatal outcomes, and further studies are needed to detect the underlying mechanism.

Association between endogenous LH level prior to progesterone administration and live birth rate in artificial frozen-thawed blastocyst transfer cycles of ovulatory women.

STUDY QUESTION: Is there an association between serum LH levels prior to progesterone administration and live birth rate (LBR) in artificial frozen-thawed embryo transfer (FET) cycles? SUMMARY ANSWER: : Low serum LH levels on the day before progesterone initiation in artificial frozen-thawed blastocyst transfer cycles of ovulatory women are associated with a lower LBR. WHAT IS KNOWN ALREADY: In artificial FET cycles, exogenous oestrogen and progesterone are administered sequentially to mimic the serum hormone pattern similar to the natural cycle. In oestrogen-only phase, the supplemental oestrogen causes thickening of the endometrium and is sometimes accompanied by a rise in serum LH. However, whether the endogenous LH level in artificial FET cycles is related to clinical outcomes remains unclear. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study including 3469 artificial frozen-thawed blastocyst transfer cycles was conducted at a tertiary-care academic medical centre between February 2014 and January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 3469 frozen blastocyst transfer cycles were stratified into four groups based on the quartiles of serum LH level before progesterone initiation: <25th percentile (LH < 8.79 mIU/ml), 25-50th percentile (8.79 ≤ LH ≤ 13.91 mIU/ml), 51-75th percentile (13.91 < LH ≤ 20.75 mIU/ml) and >75th percentile (LH > 20.75 mIU/ml). The serum LH level >75th percentile group was considered as the reference group. Patients with polycystic ovarian syndrome or other ovulatory disorders were excluded from the study. We also excluded cycles with an endometrial thickness <7 mm before progesterone initiation and patients with intrauterine adhesions and uterine abnormalities. In order to avoid the interference of BMI, all patients were divided into two categories based on the overweight threshold: BMI <25 kg/m2 and ≥25 kg/m2, and the impacts of serum LH levels on LBR were investigated separately. Univariable and multivariable logistic regression analysis were performed to adjust for potential confounders. EmpowerStats software and R-project were used to build smooth curve fitting models. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with the reference group, the implantation rate significantly decreased with low LH levels (<25th percentile) on the day before progesterone initiation (odds ratio [OR] = 0.74; 95% CI, 0.64-0.86; P = 0.001). Accounting for major covariates, low LH levels were associated with a relatively lower LBR (adjusted OR = 0.649; 95% CI, 0.531-0.794; P < 0.001), mainly due to a lower implantation rate, lower clinical pregnancy rate and higher pregnancy loss rate. Moreover, in the patients with BMI <25 kg/m2, low LH was associated with a lower LBR (P < 0.001); while in the overweight subgroup, LBR and LH were not correlated (P = 0.823). LIMITATIONS, REASONS FOR CAUTION: The main limitation of this study is its retrospective design. Owing to the relatively small number in the overweight group, the results of the overweight subgroup should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The evidence provided in this study shows the importance of serum LH levels on the day before progesterone initiation in patients undergoing artificial FET cycles. Hypothalamic dysfunction may be one of the important causes of a relatively low LH, which is related to impaired pregnancy outcomes. Serum LH levels may be used as one of the clinical indicators to predict pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): No funding and no competing interest were involved in this study. TRIAL REGISTRATION NUMBER: NA.

Up-regulated FHL2 inhibits ovulation through interacting with androgen receptor and ERK1/2 in polycystic ovary syndrome.

BACKGROUND: The ovulatory dysfunction mechanisms underlying polycystic ovary syndrome (PCOS) are not completely understood. There is no effective therapy for PCOS so far. METHODS: We measured the expression of four and a half LIM domain 2 (FHL2) and other related-genes in human granulosa cells (hGCs) from patients with and without PCOS. To minimise the heterogeneity of patients with PCOS, we only included PCOS patients meeting all three criteria according to the revised Rotterdam consensus. The in vitro effects of FHL2 on ovulatory genes and the underlying mechanisms were examined in KGN cells. The role of FHL2 in ovulation was investigated in vivo by overexpressing FHL2 in rat ovaries via intrabursal lentivirus injection. FINDINGS: Increased FHL2 and androgen receptor (AR) expression and decreased CCAAT/enhancer-binding protein ß (C/EBPß) expression were observed in hGCs from patients with PCOS. FHL2 inhibited the expression of ovulation-related genes, including phosphorylated ERK1/2, C/EBPß, COX2 and HAS2 in KGN cells. It was partially by interacting with AR to act as its co-regulator to inhibit C/EBPß expression and by binding to ERK1/2 to inhibit its phosphorylation. Moreover, FHL2 abundance in hGCs was positively correlated with the basal serum testosterone concentration of patients with PCOS, and dihydrotestosterone (DHT)-induced FHL2 upregulation was mediated by AR signalling in KGN cells. Additionally, lentiviral-mediated functional FHL2 overexpression in rat ovaries for 1 week contributed to an impaired superovulatory response, displaying decreased numbers of retrieved oocytes and a lower MII oocyte rate. 3-week FHL2 overexpression rat models without superovulation led to acyclicity and polycystic ovary morphology. INTERPRETATION: Our findings provide novel insights into the mechanisms underlying the pathogenesis of PCOS, suggesting that FHL2 could be a potential treatment target for ovulatory obstacles in PCOS. FUND: National Key Research and Development Program of China, National Natural Science Foundation, National Institutes of Health project and Shanghai Commission of Science and Technology.

Overexpression of MEF2D contributes to oncogenic malignancy and chemotherapeutic resistance in ovarian carcinoma.

The transcription factor MEF2 promotes survival in various cell types and a number of studies indicate that abnormal regulation of MEF2 is linked to oncogenicity in several carcinomas. We have found that MEF2D, a member of the MEF2 family, is upregulated in Ovarian Cancer (OC). Immunohistochemistry analysis of tumor sections of 402 OC patients revealed that MEF2D is significantly elevated at the protein level. We have also found that the expression level of MEF2D is associated with cisplatin-resistance and poor prognosis by a retrospective analysis. Furthermore, Downregulation of MEF2D by siRNA reduces proliferation and invasiveness of OC cells SKOV3 and OVCAR3, induces apoptosis in vitro, and abolishes OVCAR3 tumorigenicity in xenograft model. Mechanistic study via ChIP analysis identified two of MEF2D-targeted genes, HPSE and IKBKE, which are associated with tumor invasion and chemotherapy-resistance, in accord with MEF2D expression in OC. Remarkably, knock-down of MEF2D invariably lead to the downregulation of IKBKE and reversed cisplatin (DDP)-resistance in cisplatin-resistant cells SKOV3-DDP. Our results suggest that MEF2D promotes malignant biological behaviors and cisplatin-resistance in OC and establish MEF2D as a new therapeutic target in OC treatment.