Roles of bone morphogenetic proteins in endometrial remodeling during the human menstrual cycle and pregnancy.

BACKGROUND: During the human menstrual cycle and pregnancy, the endometrium undergoes a series of dynamic remodeling processes to adapt to physiological changes. Insufficient endometrial remodeling, characterized by inadequate endometrial proliferation, decidualization and spiral artery remodeling, is associated with infertility, endometriosis, dysfunctional uterine bleeding, and pregnancy-related complications such as preeclampsia and miscarriage. Bone morphogenetic proteins (BMPs), a subset of the transforming growth factor-ß (TGF-ß) superfamily, are multifunctional cytokines that regulate diverse cellular activities, such as differentiation, proliferation, apoptosis, and extracellular matrix synthesis, are now understood as integral to multiple reproductive processes in women. Investigations using human biological samples have shown that BMPs are essential for regulating human endometrial remodeling processes, including endometrial proliferation and decidualization. OBJECTIVE AND RATIONALE: This review summarizes our current knowledge on the known pathophysiological roles of BMPs and their underlying molecular mechanisms in regulating human endometrial proliferation and decidualization, with the goal of promoting the development of innovative strategies for diagnosing, treating and preventing infertility and adverse pregnancy complications associated with dysregulated human endometrial remodeling. SEARCH METHODS: A literature search for original articles published up to June 2023 was conducted in the PubMed, MEDLINE, and Google Scholar databases, identifying studies on the roles of BMPs in endometrial remodeling during the human menstrual cycle and pregnancy. Articles identified were restricted to English language full-text papers. OUTCOMES: BMP ligands and receptors and their transduction molecules are expressed in the endometrium and at the maternal-fetal interface. Along with emerging technologies such as tissue microarrays, 3D organoid cultures and advanced single-cell transcriptomics, and given the clinical availability of recombinant human proteins and ongoing pharmaceutical development, it is now clear that BMPs exert multiple roles in regulating human endometrial remodeling and that these biomolecules (and their receptors) can be targeted for diagnostic and therapeutic purposes. Moreover, dysregulation of these ligands, their receptors, or signaling determinants can impact endometrial remodeling, contributing to infertility or pregnancy-related complications (e.g. preeclampsia and miscarriage). WIDER IMPLICATIONS: Although further clinical trials are needed, recent advancements in the development of recombinant BMP ligands, synthetic BMP inhibitors, receptor antagonists, BMP ligand sequestration tools, and gene therapies have underscored the BMPs as candidate diagnostic biomarkers and positioned the BMP signaling pathway as a promising therapeutic target for addressing infertility and pregnancy complications related to dysregulated human endometrial remodeling.

Oral micronized progesterone versus vaginal progesterone for luteal phase support in fresh embryo transfer cycles: a multicenter, randomized, non-inferiority trial.

STUDY QUESTION: Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER: The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY: LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION: This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11-12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): -2.6%; 95% CI: -9.0% to 3.8%, P-value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: -6.4%; 95% CI: -12.6% to -0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION: The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS: Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE: May 2018. DATE OF FIRST PATIENT'S ENROLMENT: November 2018.

Identification of novel first-trimester serum biomarkers for early prediction of preeclampsia.

BACKGROUND: Preeclampsia (PE) is a leading cause of maternal and perinatal mortality and morbidity worldwide, but effective early prediction remains a challenge due to the lack of reliable biomarkers. METHODS: Based on the extensive human biobank of our large-scale assisted reproductive cohort platform, the first-trimester serum levels of 48 cytokines, total immunoglobulins (Igs), anti-phosphatidylserine (aPS) antibodies, and several previously reported PE biomarkers [including placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and activin A] were measured in 34 women diagnosed with PE and 34 matched normotensive controls. RESULTS: The PE group has significantly higher first-trimester serum levels of interleukin (IL)-2Rα, IL-9, tumor necrosis factor-ß (TNF-ß), RANTES, hepatocyte growth factor (HGF), total IgM, and total IgG, and aPS IgG optical density (OD) value, as well as lower first-trimester serum levels of PlGF and total IgA and aPS-IgG immune complexes (IC) OD value than the control group. Combining top five first-trimester serum biomarkers (total IgM, total IgG, PlGF, aPS IgG, and total IgA) achieved superior predictive value [area under the curve (AUC) and 95% confidence interval (CI) 0.983 (0.952-1.000), with a sensitivity of 100% and a specificity of 94.1%] for PE development compared to PlGF and PlGF/sFlt-1 independently [AUC and 95% CI 0.825 (0.726-0.924) and 0.670 (0.539-0.800), respectively]. CONCLUSION: We identified novel first-trimester serum biomarkers and developed an effective first-trimester prediction model using immune-related factors and PlGF for PE, which could facilitate the development of early diagnostic strategies and provide immunological insight into the further mechanistic exploration of PE.

ANGPTL4 inhibits granulosa cell proliferation in polycystic ovary syndrome by EGFR/JAK1/STAT3-mediated induction of p21.

Polycystic ovary syndrome (PCOS) is one of the most common, heterogenous endocrine disorders and is the leading cause of ovulatory obstacle associated with abnormal folliculogenesis. Dysfunction of ovarian granulosa cells (GCs) is recognized as a major factor that underlies abnormal follicle maturation. Angiopoietin-like 4 (ANGPTL4) expression in GCs differs between patients with and without PCOS. However, the role and mechanism of ANGPTL4 in impaired follicular development are still poorly understood. Here, the case-control study was designed to investigate the predictive value of ANGPTL4 in PCOS while cell experiments in vitro were set for mechanism research. Results found that ANGPTL4 levels in serum and in follicular fluid, and its expression in GCs, were upregulated in patients with PCOS. In KGN and SVOG cells, upregulation of ANGPTL4 inhibited the proliferation of GCs by blocking G1/S cell cycle progression, as well as the molecular activation of the EGFR/JAK1/STAT3 cascade. Moreover, the STAT3-dependent CDKN1A(p21) promoter increased CDKN1A transcription, resulting in remarkable suppression effect on GCs. Together, our results demonstrated that overexpression of ANGPTL4 inhibited the proliferation of GCs through EGFR/JAK1/STAT3-mediated induction of p21, thus providing a novel epigenetic mechanism for the pathogenesis of PCOS.

Risk factors for clinical pregnancy loss after IVF in women with PCOS.

RESEARCH QUESTION: Which factors are associated with the risk of clinical pregnancy loss in women with polycystic ovary syndrome (PCOS) undergoing IVF? DESIGN: Case-control study nested in a multicentre randomized trial comparing live birth rates between fresh and frozen embryo transfer in women with PCOS. Women with the outcome of clinical pregnancy loss were selected as the case group, those with live birth as the control group. Parameters before IVF treatment and variables during ovarian stimulation and embryo transfer were compared. RESULTS: Women with clinical pregnancy loss had higher maternal body mass index (BMI, P = 0.010), anti-Müllerian hormone (AMH, P = 0.032), 2-h glucose concentration after 75 g oral glucose tolerance test (OGTT, P = 0.025), and a higher proportion of fresh embryo transfers (P = 0.001). There were significant interactions between the types of transfer and antral follicle count (AFC, P = 0.013), 2-h glucose concentration after OGTT (P = 0.024) on clinical pregnancy loss in PCOS, indicating that these factors may have different effects on pregnancy loss after fresh versus frozen embryo transfer. When the multivariable logistic regression analysis was stratified by the fresh or frozen embryo transfer, AFC (adjusted odds ratio [aOR] 1.03, 95% confidence interval [CI] 1.01-1.05) was a risk factor for clinical pregnancy loss after fresh embryo transfer, while 2-hour glucose concentration after OGTT (aOR 1.13, 95% CI 1.01-1.25) was associated with clinical pregnancy loss in frozen embryo transfer (FET) cycles. CONCLUSIONS: In women with PCOS, fresh embryo transfer, higher BMI, AFC and 2-h glucose concentration after OGTT were risk factors for clinical pregnancy loss. FET may be a better choice to decrease the risk of clinical pregnancy loss, especially for those with higher AFC. During FET, 2-h glucose after OGTT appears to be associated with clinical pregnancy loss and warrants close monitoring.

Ovulation induction regimens are associated with a higher rate of livebirth after frozen single-blastocyst transfer among women with polycystic ovary syndrome.

Background: Hormone replacement therapy (HRT) regimen was suggested to be associated with a decreased rate of livebirth and a higher risk of hypertensive disorders of pregnancy (HDP) after frozen cleavage stage embryo transfer in women with polycystic ovary syndrome (PCOS). With the dramatically increased use of elective single embryo transfer, there is great need to explore the impacts of different endometrial preparation regimens on frozen single-blastocyst transfer in women with PCOS. Methods: In this study, a total of 3941 women who diagnosed with PCOS and underwent single-blastocyst transfer during their first cycles of frozen embryo transfer (FET) between March 2012 and December 2020 were included. We retrospectively compared the pregnancy and neonatal outcomes after frozen single-blastocyst transfer with endometrial preparation by HRT regimen (n = 3540), ovulation induction by human menopausal gonadotropin (hMG) regimen (n = 226), and ovulation induction by letrozole regimen (n = 175). Results: After adjustment for confounders with multivariable logistic regression, the hMG regimen group [(58.4% vs. 49.6%; adjusted odds ratio (aOR): 1.43; 95% confidence interval (CI): 1.09-1.89)] and letrozole regimen group (58.9% vs. 49.6%; aOR: 1.42; 95% CI: 1.04-1.93) were associated with a higher rate of livebirth (primary outcome), compared with the group with HRT regimen. As to the secondary outcomes, the rate of pregnancy loss in the hMG regimen group (22.8% vs. 30.3%; aOR: 0.69; 95% CI: 0.48-1.00) and letrozole regimen group (16.9% vs. 30.3%; aOR: 0.48; 95% CI: 0.30-0.78) was also lower than that in the HRT regimen group. The pregnancy outcomes between the hMG regimen group and the letrozole regimen group were similar. We did not observe significant difference in the incidences of maternal and neonatal complications among these three groups. Conclusion: Ovulation induction regimen with letrozole or hMG for endometrial preparation was associated with a higher livebirth rate and a lower pregnancy loss rate in frozen single-blastocyst transfer cycles among women with PCOS.

The effect of different endometrial preparations on women with polycystic ovary syndrome undergoing initial frozen embryo transfer: A historical cohort analysis.

INTRODUCTION: Frozen embryo transfer is associated with a higher rate of live birth and a lower risk for ovarian hyperstimulation syndrome in women with polycystic ovary syndrome (PCOS) compared with fresh embryo transfer. The aim of this study is to assess the optimal endometrial preparation protocol for women with PCOS undergoing frozen embryo transfer. MATERIAL AND METHODS: We conducted a historical cohort analysis of 1720 women with PCOS who underwent the "freeze-all" strategy between August 2014 and August 2017 because of their high risk for ovarian hyperstimulation syndrome. Three endometrial preparation protocols were used: natural cycle (NC; n = 191), which relies on the dominant follicle to secrete estrogen that then promotes endometrial growth; ovarian stimulation (OS; n = 96), which induces follicle growth using low doses of human menopausal gonadotropin; and hormone replacement (HRT; n = 1433), which uses exogenous estradiol to promote endometrial growth. The primary outcome was live birth. RESULTS: For women who received a single embryo transfer, the live birth rates for the NC, OS, and HRT groups were 62.4%, 65.0%, and 52.2%, respectively. The live birth rate in the HRT group was significantly lower than that seen in the OS and NC groups (P = .009). The clinical pregnancy rates of the three groups were 72.3%, 73.8%, and 64.9%, respectively; this difference did not reach statistical significance (P = .071). CONCLUSIONS: The rate of live birth with the NC and OS regimens was higher than with the HRT protocol in women with PCOS who undergo single-blastocyst frozen embryo transfer.

Transmission of polycystic ovary syndrome susceptibility single-nucleotide polymorphisms and their association with phenotype changes in offspring.

STUDY QUESTION: Does the inheritance of polycystic ovary syndrome (PCOS) susceptibility single-nucleotide polymorphism affect the phenotype of offspring? SUMMARY ANSWER: Male offspring who inherit PCOS-related genetic variations from PCOS mothers were more susceptible to developing the metabolic abnormality in their later life. WHAT IS KNOWN ALREADY: Genetic factors are considered the major etiology of PCOS. Previous studies have highlighted that offspring of women with PCOS had an increased risk of the same disease or PCOS-like symptoms. STUDY DESIGN, SIZE, DURATION: The study involved 172 children born to women with PCOS and 529 children born to non-PCOS women. All offspring were conceived by assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: The offspring ranged from 1 to 8 years old. Metabolic phenotype analyses were performed in offspring aged from 2 to 8 (N = 619). Sanger sequencing, TaqMan and Sequenom MassARRAY were used to sequence the samples. MAIN RESULTS AND THE ROLE OF CHANCE: In male offspring, the fasting insulin (FINS) (P = 0.037) homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.038) and the homeostasis model assessment of pancreatic beta-cell function (HOMA-ß) (P = 0.038) levels were higher in offspring of PCOS mothers compared to controls. In female offspring, PCOS offspring had a significantly higher anti-Müllerian hormone levels (P = 0.001) compared to those from control mothers. In male offspring of PCOS mothers, subjects with a T allele at rs2349415 in the gene FSHR had higher FINS (P = 0.023), HOMA-IR (P = 0.030) and HOMA-ß levels (P = 0.013) than those in the homozygous CC group. The same increased trend in FINS, HOMA-IR and HOMA-ß levels could be found in the CC and TC group in rs2268361 located in gene FSHR compared to the TT group (P = 0.029, P = 0.030, P = 0.046, respectively). As for rs10818854 in the DENND1A gene, the AA and AG group had a higher FINS (P = 0.037) and HOMA-ß (P = 0.008) levels than the homozygous CC group. LIMITATIONS, REASONS FOR CAUTION: Firstly, the offspring may be too young to see any phenotype changes. Secondly, this study only analyzed the differences of genotype frequency using the dominant model instead of all three models due to the limited sample size of the homozygous model. The results, therefore, should be replicated and performed in a larger sample size population. Thirdly, environmental impacts cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: The findings presented in this thesis add to our understanding the changes in offspring born to PCOS women and remind us to consider early intervention to avoid more severe effects. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China 2017YFC1001000 (to Z.-J.C.), the National Natural Science Foundation of China 81430029 (to Z.-J.C.), 81622021 and 31571548 (to H.Z.), the National Natural Science Foundation of Shandong Province JQ201816 (to H.Z.) and Shandong Provincial Key Research and Development Program 2017G006036 (to L.-L.C.) and 2018YFJH0504 (to Z.-J.C.). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Live birth after a freeze-only strategy versus fresh embryo transfer in three randomized trials considering progesterone concentration.

RESEARCH QUESTION: Is there a difference in live birth rate between a freeze-only strategy and fresh embryo transfer, and what is the effect of varying progesterone concentrations on the day of human chorionic gonadotrophin (HCG) administration? DESIGN: A secondary analysis of data from three randomized trials comparing the live birth rate after elective frozen versus fresh embryo transfer, which respectively enrolled 1508 women with polycystic ovary syndrome, 2157 ovulatory women who underwent cleavage-stage embryo transfer and 1650 ovulatory women who underwent single blastocyst transfer. Women were randomly assigned to the frozen or fresh embryo transfer group in the original trials. The primary outcome was live birth rate after the initial embryo transfer. RESULTS: The live birth rate after a freeze-only strategy was consistently higher than fresh embryo transfer at any progesterone concentration on the day of HCG administration. Nonetheless, the between-group difference in live birth rate after frozen versus fresh embryo transfer was greater in women with progesterone concentrations ≥1.14 ng/ml (52.7% versus 37.3%, odds ratio (OR) 1.88, 95% confidence interval (CI) 1.55-2.27, P = 7.89 â€¯×  10-11) than in women with progesterone concentrations <1.14 ng/ml (53.3% versus 48.1%, OR 1.23, 95% CI 1.08-1.41, P = 0.002). In women with progesterone concentration ≥1.14 ng/ml, frozen embryo transfer also resulted in higher rates of conception and clinical pregnancy than fresh embryo transfer. CONCLUSION: In women with normal or high ovarian response, a freeze-only strategy resulted in a higher live birth rate than fresh embryo transfer, irrespective of progesterone concentration. Moreover, women with progesterone concentration ≥1.14 ng/ml may benefit more from a freeze-only strategy.

Effects of oral contraceptive pretreatment on IVF outcomes in women following a GnRH agonist protocol.

RESEARCH QUESTION: Does oral contraceptive pretreatment impact IVF-embryo transfer cycle outcomes in women following the gonadotrophin-releasing hormone agonist (GnRHa) protocol? DESIGN: This retrospective study was designed to compare cycle outcomes after oral contraceptive pretreatment versus the standard protocol in women within the GnRHa long protocol or the GnRHa short protocol. A total of 2052 women undergoing their first IVF treatment with the GnRHa long protocol and 3557 women with the GnRHa short protocol between 2012 and 2017 were enrolled. RESULTS: No significant differences in the rates of clinical pregnancy (long protocol: 49.2% versus 46.7%; short protocol: 39.4% versus 38.0%) or live birth (long protocol: 44.3% versus 41.3%; short protocol: 32.8% versus 31.4%) after fresh embryo transfer were observed between the oral contraceptive group and the control group in either the long protocol or the short protocol. CONCLUSIONS: Oral contraceptive pretreatment has no effect on IVF outcomes in either the GnRHa long protocol or short protocol.

Influence of metabolic syndrome on female fertility and in vitro fertilization outcomes in PCOS women.

OBJECTIVE: With a high incidence of insulin resistance, central obesity and dyslipidemia, women with polycystic ovary syndrome are susceptible to metabolic syndrome (MetS). Our objective was to explore whether metabolic syndrome had an effect on overall female fertility and in vitro fertilization outcomes in infertile women with polycystic ovary syndrome. STUDY DESIGN: This was a secondary analysis of a multicenter randomized trial in 1508 women with polycystic ovary syndrome, which was originally designed to compare the live birth rate after fresh-embryo transfer vs frozen embryo transfer (Frefro-PCOS). At baseline, metabolic parameters, including body mass index, waist and hip circumference, blood pressure, lipid profile, fasting, and 2 hour glucose and insulin levels after a 75 g oral glucose tolerance test were measured. All subjects were divided into a metabolic syndrome group (metabolic syndrome) and absence of metabolic syndrome group (nonmetabolic syndrome) according to diagnostic criteria. Descriptive statistics and logistic regression models tested the association between metabolic syndrome and overall fertility and in vitro fertilization cycle stimulation characteristics and clinical outcomes. RESULTS: Metabolic syndrome was identified in 410 of 1508 infertile women with polycystic ovary syndrome (27.2%). Patients with metabolic syndrome had longer infertility duration (4.0 ± 2.2 vs 3.7 ± 2.2, P = .004) compared with those without metabolic syndrome. During ovarian stimulation, those with metabolic syndrome required significantly higher and longer doses of gonadotropin and had lower peak estradiol level, fewer retrieved oocytes, available embryos, a lower oocyte utilization rate, and ovarian hyperstimulation syndrome than those with nonmetabolic syndrome. The cumulative live birth rate did not show a significant between-group difference (57.8% vs 62.2%, P = .119). Multivariate logistic regression analysis adjusted for age, duration of infertility, body mass index, thyroid-stimulating hormone, metabolic syndrome group, homeostatic model assessment of insulin resistance, metformin utilization, number of available embryos, and embryos transferred showed that the number of embryos transferred and the number of available embryos were positively but metabolic syndrome negatively associated with the cumulative live birth rate (odds ratio, 2.18, 1.10, and 0.70, respectively, P < .05). CONCLUSION: Women with polycystic ovary syndrome with metabolic syndrome have a negative impact from female fecundity, and this suggests an adverse effect on in vitro fertilization cycle stimulation characteristics and clinical outcomes.

The HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome.

CONTEXT: The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown. OBJECTIVE: We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation. PATIENTS AND CELLS: mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study. MAIN OUTCOME MEASURES: mRNA expression in ovarian GCs was measured using quantitative RT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study. RESULTS: HMGA2 and IGF2 mRNA binding protein 2 (IMP2) were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. Cyclin D2 and SERPINE1 mRNA binding protein 1 were regulated by IMP2 and were highly expressed in women with PCOS. CONCLUSIONS: The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS.

The Effect of Supraphysiological Estradiol on Pregnancy Outcomes Differs Between Women With PCOS and Ovulatory Women.

Context: Supraphysiological estradiol exposure after ovarian stimulation may disrupt embryo implantation after fresh embryo transfer. Women with polycystic ovary syndrome (PCOS), who usually overrespond to ovarian stimulation, have a better live birth rate after frozen embryo transfer (FET) than after fresh embryo transfer; however, ovulatory women do not. Objective: To evaluate whether the discrepancy in live birth rate after fresh embryo transfer vs FET between these two populations is due to the variation in ovarian response (i.e., peak estradiol level or oocyte number). Design, Setting, Patients, Intervention(s), and Main Outcome Measure(s): This was a secondary analysis of data from two multicenter randomized trials with similar study designs. A total of 1508 women with PCOS and 2157 ovulatory women were randomly assigned to undergo fresh or FET. The primary outcome was live birth. Results: Compared with fresh embryo transfer, FET resulted in a higher live birth rate (51.9% vs 40.7%; OR, 1.57; 95% CI, 1.22 to 2.03) in PCOS women with peak estradiol level >3000pg/mL but not in those with estradiol level ≤3000 pg/mL. In women with PCOS who have ≥16 oocytes, FET yielded a higher live birth rate (54.8% vs 42.1%; OR, 1.67; 95% CI, 1.20 to 2.31), but this was not seen in those with <16 oocytes. In ovulatory women, pregnancy outcomes were similar after fresh embryo transfer and FET in all subgroups. Conclusions: Supraphysiological estradiol after ovarian stimulation may adversely affect pregnancy outcomes in women with PCOS but not in ovulatory women.

Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial.

OBJECTIVE: To evaluate the effect of frozen embryo transfer on maternal and neonatal complications of singleton and twin pregnancies compared with fresh embryo transfer in women with polycystic ovary syndrome (PCOS). DESIGN: A secondary analysis of a multicenter, randomized, controlled trial comparing live birth after frozen vs. fresh embryo transfer (FreFro-PCOS). SETTING: Reproductive medicine centers. PATIENT(S): A total of 1,508 patients with a diagnosis of PCOS who were undergoing IVF were enrolled. INTERVENTION(S): On day of oocyte retrieval, eligible patients were randomized to the fresh or frozen embryo transfer groups. Up to two embryos were transferred in both groups. All pregnancies were followed up until delivery. MAIN OUTCOME MEASURE(S): Gestational diabetes mellitus, pre-eclampsia, preterm birth, small for gestational age, and large for gestational age. RESULT(S): The risks of gestational diabetes mellitus, preterm birth, and small for gestational age were comparable between the frozen and fresh embryo transfer groups in both singleton and twin births. However, singleton infants born after frozen embryo transfer were more likely to be large for gestational age (25.2% vs. 17.5%; relative risk 1.44, 95% confidence interval 1.01-2.07, P=.044) than those born after fresh embryo transfer. Twin pregnancy after frozen embryo transfer had a higher risk of pre-eclampsia (12.0% vs. 2.8%; relative risk 4.31, 95% confidence interval 1.27-14.58, P=.009) than those after fresh embryo transfer. CONCLUSION(S): In women with PCOS, frozen embryo transfer resulted in an increased risk of large for gestational age in singleton pregnancy and a higher risk of pre-eclampsia in twin pregnancy. CLINICAL TRIAL REGISTRATION NUMBER: NCT01841528.

Effect of Preconception Impaired Glucose Tolerance on Pregnancy Outcomes in Women With Polycystic Ovary Syndrome.

Context: Women with polycystic ovary syndrome (PCOS) commonly have intrinsic insulin resistance and are recommended to undergo an oral glucose tolerance test (OGTT) for diabetes screening. However, the effect of preconception impaired glucose tolerance (IGT) on pregnancy is still unclear. Objective: To prospectively assess the effect of preconception IGT on pregnancy outcomes. Design, Setting, Patients, Interventions, and Main Outcome Measures: This was a secondary analysis of a multicenter randomized trial in 1508 women with PCOS comparing live birth and obstetric complications between fresh and frozen embryo transfer. At baseline, fasting and 2-hour glucose and insulin levels after 75-g OGTT were measured. Results: Women with preconception IGT had higher risks of gestational diabetes in both singleton pregnancy [9.5% vs 3.2%; odds ratio (OR) 3.13; 95% confidence interval (CI) 1.23to 7.69] and twin pregnancy (20.0% vs 3.2%; OR 7.69; 95% CI 2.78 to 20.00) than women with normoglycemia. Preconception IGT was associated with a higher risk of large for gestational age in singleton newborns compared with normoglycemia (34.7% vs 19.8%; OR 2.13; 95% CI 1.19 to 3.85) or isolated impaired fasting glucose (i-IFG) (34.7% vs 15.4%; OR 2.94; 95% CI 1.33 to 6.25). Women with preconception IGT had a higher singleton pregnancy loss rate than women with i-IFG (31.4% vs 17.5%; OR 2.17; 95% CI 1.11 to 4.17). After adjusting for age, body mass index, duration of infertility, total testosterone level, and treatment groups (frozen vs fresh embryo transfer), these associations remained. Conclusions: Preconception IGT, independent from BMI, was associated with adverse pregnancy outcome compared with i-IFG and normoglycemia.

Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome.

STUDY QUESTION: Do oral contraceptives (OCs) and progestins impact live birth rate of IVF when used for cycle scheduling in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: OCs used for scheduling IVF cycle were associated with lowered rates of pregnancy and live birth after fresh embryo transfer, whereas progestins used for this purpose yield higher rates of pregnancy and live birth than OCs. WHAT IS KNOWN ALREADY: Due to oligo-menorrhea in PCOS, OCs and progestin are extensively used to schedule the start of an IVF cycle in women with PCOS. Little is known about the effect of such pretreatments on outcomes, especially, the rate of live birth. STUDY DESIGN, SIZE, DURATION: This was a nested cohort study and secondary analysis of a multicenter randomized trial, which was designed to compare live birth rate after fresh embryo transfer vs frozen embryo transfer (FET) in women with PCOS (Frefro-PCOS). A total of 1508 women were enrolled from 14 centers between June 2013 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: At the discretion of local investigators, subjects were instructed to wait for spontaneous menses (Control group, n = 323), or were prescribed progestins (P group, n = 283) or OCs (OCs group, n = 902) to induce menstruation prior to the start of ovarian stimulation. GnRH antagonist protocol was initiated at Day 2 or 3 of induced or spontaneous menses cycle. The rates of pregnancy, pregnancy loss and live birth after either fresh embryo transfer or FET were compared among these three groups. MAIN RESULTS AND THE ROLE OF CHANCE: With fresh embryo transfer, women with OC-induced menses had lower rates of clinical pregnancy (48.8% vs 63.6%, relative rate (RR): 0.77, 95% CI: 0.66-0.89) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61-0.92) than women with spontaneous menses. With freeze-all and deferred FET, women with OC-induced menses had a similar pregnancy rate but a higher pregnancy loss rate (27.7% vs 13.0%, RR: 2.13, 95% CI: 1.28-3.52) after FET than women with spontaneous menses. The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses was 49.4%, 50.7% and 60.2%, respectively (P = 0.06). Progestin-induced menses was associated with similar rates of pregnancy, pregnancy loss and live birth after transfer of either fresh or frozen embryos compared with spontaneous menses. Multivariate logistic regression analysis showed that OCs used for menses induction was associated with lower rate of live birth. LIMITATIONS, REASONS FOR CAUTION: The methods for menses induction were not assigned randomly, thus selection bias was highly likely because of the study design and significant differences that were observed in the baseline characteristics of the women in the different groups. The mean BMI in this study population was relatively normal; the applicability of this result to obese PCOS women needs to be evaluated in further study. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. Further randomized controlled studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTERESTS: This study was funded by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), National Natural Science Foundation of China (81471428) and Thousand Talents Program (Drs Legro and Zhang H). Dr Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures. TRIAL REGISTRATION NUMBER: Frefro-PCOS was registered at Clinicaltrials.gov: NCT01841528.

Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome.

BACKGROUND: The transfer of fresh embryos is generally preferred over the transfer of frozen embryos for in vitro fertilization (IVF), but some evidence suggests that frozen-embryo transfer may improve the live-birth rate and lower the rates of the ovarian hyperstimulation syndrome and pregnancy complications in women with the polycystic ovary syndrome. METHODS: In this multicenter trial, we randomly assigned 1508 infertile women with the polycystic ovary syndrome who were undergoing their first IVF cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. After 3 days of embryo development, women underwent the transfer of up to two fresh or frozen embryos. The primary outcome was a live birth after the first embryo transfer. RESULTS: Frozen-embryo transfer resulted in a higher frequency of live birth after the first transfer than did fresh-embryo transfer (49.3% vs. 42.0%), for a rate ratio of 1.17 (95% confidence interval [CI], 1.05 to 1.31; P=0.004). Women who underwent frozen-embryo transfer also had a lower frequency of pregnancy loss (22.0% vs. 32.7%), for a rate ratio of 0.67 (95% CI, 0.54 to 0.83; P<0.001), and of the ovarian hyperstimulation syndrome (1.3% vs. 7.1%), for a rate ratio of 0.19 (95% CI, 0.10 to 0.37; P<0.001), but a higher frequency of preeclampsia (4.4% vs. 1.4%), for a rate ratio of 3.12 (95% CI, 1.26 to 7.73; P=0.009). There were no significant between-group differences in rates of other pregnancy and neonatal complications. There were five neonatal deaths in the frozen-embryo group and none in the fresh-embryo group (P=0.06). CONCLUSIONS: Among infertile women with the polycystic ovary syndrome, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer. (Funded by the National Basic Research Program of China and others; ClinicalTrials.gov number, NCT01841528.).

Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature.

STUDY QUESTION: What is the direct genetic contribution of the polycystic ovary syndrome (PCOS) susceptibility single nucleotide polymorphisms (SNPs), identified by previous genome-wide association studies (GWAS) to the definitive clinical features of the syndrome? SUMMARY ANSWER: Each single PCOS clinical feature had a specific genetic association, and rs4385527 in the chromosome 9 open reading frame 3 (C9orf3) conferred a particular risk to the three defined PCOS clinical features in this study, which suggested its fundamental role in the etiology of PCOS. WHAT IS KNOWN ALREADY: PCOS is a heterogeneous disorder characterized by anovulation (OA), hyperandrogenism (HA) and polycystic ovary morphology (PCOM). Two previous GWAS in China have identified 15 independent susceptibility SNPs related to PCOS (PCOS-SNPs). However, little is known about the candidate gene of each clinical feature. STUDY DESIGN, SIZE, DURATION: Case-control study. Three independent groups of women were recruited from 2010 to 2012: 746 subjects with OA only, 278 subjects with HA only and 536 subjects with PCOM only. A total of 1790 healthy women with none of the above pathological characteristics were also enrolled as control subjects during the same time period. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were women of reproductive age. Genotype and allelic frequencies of 15 PCOS-SNPs were determined in all subjects using direct sequencing and Sequenom Arrays. The allelic frequencies of each case group were compared with the controls. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01, <0.001 and <0.05, respectively); rs4385527 in C9orf3 was strongly associated with HA (Padjust< 0.001); variants in the thyroid adenoma associated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01, <0.001, <0.05 and <0.001, respectively). LIMITATIONS, REASONS FOR CAUTION: The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent. WIDER IMPLICATIONS OF THE FINDINGS: The present study indicates a potential common genetic basis of three PCOS clinical features. Other specific associated genes may play a synergistic role, leading to heterogeneous pathophysiological changes. Additionally, the increased frequency of PCOS-risk alleles in women with single PCOS clinical features suggests that these subjects have an elevated risk of developing the syndrome, although they cannot be currently diagnosed. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700, 2011CB944502), the National Key Technology Research and Development Program(2011BAI17B00), the National Natural Science Foundation of China (81430029, 81201441, 81490743, 31371453), the Scientific Research Foundation of Shandong Province of Outstanding Young Scientist (2012BSE27089) and the Fundamental Research Funds of Shandong University(2014GN025). There were no competing interests.

Live birth after fresh embryo transfer vs elective embryo cryopreservation/frozen embryo transfer in women with polycystic ovary syndrome undergoing IVF (FreFro-PCOS): study protocol for a multicenter, prospective, randomized controlled clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) patients are at increased risk of pregnancy complications, which may impair pregnancy outcome. Transfer of fresh embryos after superovulation may lead to abnormal implantation and placentation and further increase risk for pregnancy loss and complications. Some preliminary data suggest that elective embryo cryopreservation followed by frozen-thawed embryo transfer into a hormonally primed endometrium could result in a higher clinical pregnancy rate than that achieved by fresh embryo transfer. METHODS/DESIGN: This study is a multicenter, prospective, randomized controlled clinical trial (1:1 treatment ratio of fresh vs. elective frozen embryo transfers).. A total of 1,180 infertile PCOS patients undergoing the first cycle of in vitro fertilization (IVF) or intracytoplasmic sperm injection will be enrolled and randomized into two parallel groups. Participants in group A will undergo fresh embryo transfer on day 3 after oocyte retrieval, and participants in group B will undergo elective embryo cryopreservation after oocyte retrieval and frozen-thawed embryo transfer in programmed cycles. The primary outcome is the live birth rate. Our study is powered at 80 to detect an absolute difference of 10 at the significance level of 0.01 based on a two-sided test. DISCUSSION: We hypothesize that elective embryo cryopreservation and frozen-thawed embryo transfer will reduce the incidence of pregnancy complications and increase the live birth rate in PCOS patients who need IVF to achieve pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01841528.