Serum and follicular fluid metabolome and markers of ovarian stimulation.

STUDY QUESTION: What metabolic pathways and metabolites in the serum and follicular fluid are associated with peak estradiol levels and the number of mature oocytes? SUMMARY ANSWER: In the serum metabolome, mostly fatty acid and amino acid pathways were associated with estradiol levels and mature oocytes while in the follicular fluid metabolome, mostly lipid, vitamin, and hormone pathways were associated with peak estradiol levels and mature oocytes. WHAT IS KNOWN ALREADY: Metabolomics has identified several metabolic pathways and metabolites associated with infertility but limited data are available for ovarian stimulation outcomes. STUDY DESIGN, SIZE, DURATION: A prospective cohort study of women undergoing IVF from 2009 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 125 women undergoing a fresh IVF cycle at a fertility clinic in the Northeast United States who provided a serum and follicular fluid sample. Untargeted metabolomics profiling was conducted using liquid chromatography with high-resolution mass spectrometry in two chromatography columns (C18 and hydrophilic interaction chromatography (HILIC)). The main ovarian stimulation outcomes were peak serum estradiol levels and number of mature oocytes. We utilized adjusted generalized linear regression models to identify significant metabolic features. Models were adjusted for age,BMI, initial infertility diagnosis, and ovarian stimulation protocol. We then conducted pathway analysis using mummichog and metabolite annotation using level-1 evidence. MAIN RESULTS AND ROLE OF CHANCE: In the serum metabolome, 480 and 850 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively. Additionally, 437 and 538 features were associated with mature oocytes in the C18 and HILIC columns, respectively. In the follicular fluid metabolome, 752 and 929 features were associated with peak estradiol levels in the C18 and HILIC columns, respectively, Additionally, 993 and 986 features were associated with mature oocytes in the C18 and HILIC columns, respectively. The most common pathways associated with peak estradiol included fatty acids (serum and follicular fluid), hormone (follicular fluid), and lipid pathways (follicular fluid). The most common pathways associated with the number of mature oocytes retrieved included amino acids (serum), fatty acids (serum and follicular fluid), hormone (follicular fluid), and vitamin pathways(follicular fluid). The vitamin D3 pathway had the strongest association with both ovarian stimulation outcomes in the follicularfluid. Four and nine metabolites were identified using level-1 evidence (validated identification) in the serum and follicular fluid metabolomes, respectively. LIMITATIONS, REASONS FOR CAUTION: Our sample was majority White and highly educated and may not be generalizable to thewider population. Additionally, residual confounding is possible and the flushing medium used in the follicular fluid could have diluted our results. WIDER IMPLICATIONS OF THE FINDINGS: The pathways and metabolites identified by our study provide novel insights into the biologicalmechanisms in the serum and follicular fluid that may underlie follicular and oocyte development, which could potentially be used to improve ovarian stimulation outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the following grants from the National Institute of Environmental Health Sciences (P30-ES019776, R01-ES009718, R01-ES022955, P30-ES000002, R00-ES026648, and T32-ES012870), and National Institute of Diabetes and Digestive and Kidney Diseases (P30DK046200). The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Effect of the ratios of estradiol increase on the outcome of in vitro fertilization-embryo transfer with antagonist regimens: a single center retrospective cohort study.

BACKGROUND: The outcome of in vitro fertilization-embryo transfer (IVF) is often determined according to follicle and estradiol levels following gonadotropin stimulation. In previous studies, although most of them analyzed the estrogen level from ovaries or the average estrogen level of a single follicle, there was no study on the ratio of estrogen increase, which was also correlated with pregnancy outcomes in the clinic. This study aimed to make timely adjustments to follow-up medication to improve clinical outcomes based on the potential value of estradiol growth rate. METHODS: We comprehensively analyzed estrogen growth during the entire ovarian stimulation period. Serum estradiol levels were measured on the day of gonadotropin treatment (Gn1), five days later (Gn5), eight days later (Gn8), and on the trigger day (HCG). This ratio was used to determine the increase in estradiol levels. According to the ratio of estradiol increase, the patients were divided into four groups: A1 (Gn5/Gn1 ≤ 6.44), A2 (6.44 < Gn5/Gn1 ≤ 10.62), A3 (10.62 < Gn5/Gn1 ≤ 21.33), and A4 (Gn5/Gn1 > 21.33); B1 (Gn8/Gn5 ≤ 2.39), B2 (2.39 < Gn8/Gn5 ≤ 3.03), B3 (3.03 < Gn8/Gn5 ≤ 3.84), and B4 (Gn8/Gn5 > 3.84). We analyzed and compared the relationship between data in each group and pregnancy outcomes. RESULTS: In the statistical analysis, the estradiol levels of Gn5 (P = 0.029, P = 0.042), Gn8 (P < 0.001, P = 0.001), and HCG (P < 0.001, P = 0.002), as well as Gn5/Gn1 (P = 0.004, P = 0.006), Gn8/Gn5 (P = 0.001, P = 0.002), and HCG/Gn1 (P < 0.001, P < 0.001) both had clinical guiding significance, and lower one significantly reduced the pregnancy rate. The outcomes were positively linked to groups A (P = 0.036, P = 0.043) and B (P = 0.014, P = 0.013), respectively. The logistical regression analysis revealed that group A1 (OR = 0.376 [0.182-0.779]; P = 0.008*, OR = 0.401 [0.188-0.857]; P = 0.018*) and B1 (OR = 0.363 [0.179-0.735]; P = 0.005*, OR = 0.389 [0.187-0.808]; P = 0.011*) had opposite influence on outcomes. CONCLUSION: Maintaining a serum estradiol increase ratio of at least 6.44 on Gn5/Gn1 and 2.39 on Gn8/Gn5 may result in a higher pregnancy rate, especially in young people.

Live birth associated with peak serum estradiol levels in letrozole intrauterine insemination cycles.

OBJECTIVE: To identify whether the serum estradiol (E2) level on the day of human chorionic gonadotropin (hCG) trigger or luteinizing hormone (LH) surge (hCG-LH) was associated with the live birth rate (LBR) during ovulation induction (OI) or controlled ovarian hyperstimulation with letrozole followed by intrauterine insemination (IUI). DESIGN: Retrospective cohort study. SETTING: Large, multicenter private practice. PATIENT(S): A total of 2,368 OI-IUI cycles in patients treated with letrozole followed by IUI were evaluated from January 1, 2014, to July 31, 2019. INTERVENTION(S): Ovulation induction with letrozole, followed by autologous IUI. MAIN OUTCOME MEASURE(S): The primary outcome measure was the LBR as a function of the serum E2 level at the time of hCG administration or LH surge, adjusting for age, body mass index, the largest follicle diameter, and the number of follicles ≥14 mm in diameter. The clinical pregnancy rate as a function of the E2 level, pregnancy rate as a function of the lead follicle diameter, and pregnancy loss rates were the secondary outcome variables. RESULT(S): A total of 2,368 cycles met the inclusion criteria. Outcomes were evaluated at the 25th (E2 level, 110 pg/mL), 50th (157 pg/mL), 75th (225 pg/mL), and 90th (319 pg/mL) percentiles. The LBRs ranged from 9.4% to 11.1% in the lower E2 cohorts and from 12.5% to 13.5% in the higher E2 cohorts. The LBR was significantly greater in the cohort of women with higher E2 levels in all percentile comparisons except for the 90th percentile. The mean periovulatory follicle diameter of ≥20 or <20 mm was not independently associated with the LBR or clinical pregnancy rate, despite a significantly higher mean E2 level in the larger follicle group. CONCLUSION(S): In letrozole OI cycles followed by IUI, lower LBRs and clinical pregnancy rates were found in women with lower E2 levels than in those with higher E2 levels at the 25th, 50th, and 75th percentile E2 level quartiles. Where possible, delaying hCG trigger until the E2 level increases after aromatase inhibition and approaches the physiologic periovulatory level may improve the pregnancy rates with letrozole followed by IUI.

The Effects of Follicular Fluid 25(OH)D Concentration on Intrafollicular Estradiol Level, Oocyte Quality, and Fertilization Rate in Women Who Underwent IVF Program.

Objective: 25(OH)D (Vitamin D) has been investigated for its role in the process of folliculogenesis and thus affects the quality of oocyte produced by in vitro fertilization. Our aims were to investigate the effects of 25(OH)D levels in follicular fluid, follicular estradiol level, successful fertilization rate in IVF treatment and the correlation between 25(OH)D levels in follicular fluid with the oocyte quality. Design and Setting: This is an analytic observational study with cross-sectional design conducted between September-November 2018 in two fertility clinics at tertiary hospitals in Bandung, Indonesia. Participants: The inclusion criteria were women aged 20-35 years who underwent controlled ovarian stimulation in IVF program with normal ovarian reserve and normal BMI. Eligible women were divided into two groups based on their 25(OH)D levels: low and high. Results: There was a significant difference in oocyte quality (p = 0.03) and follicular estradiol levels (p = 0.02) between the two categories of 25(OH)D levels. High level of 25(OH)D has significantly higher level in comparison with the low level of 25(OH)D. No significant differences were found in terms of successful fertilization rate (p = 0.13). High level of 25(OH)D has higher successful fertilization rate compared to low level of 25(OH)D (71.8% vs 55.26%). A significant positive correlation between 25(OH)D level in follicular fluid and oocyte quality was also found (r = 0.32, p = 0.01). Conclusion: Women with higher level of 25(OH)D are significantly more likely to have high-quality oocyte and follicular estradiol levels than those with low level of 25(OH)D, although there are no significant results for its relation to successful fertilization rate.

Association between serum estradiol level on day of progesterone start and outcomes from frozen blastocyst transfer cycles utilizing oral estradiol.

PURPOSE: Supraphysiologic serum estradiol levels may negatively impact the likelihood of conception and live birth following IVF. The purpose of this study is to determine if there is an association between serum estradiol level on the day of progesterone start and clinical outcomes following programmed frozen blastocyst transfer cycles utilizing oral estradiol. METHODS: This is a retrospective cohort study at an academic fertility center analyzing 363 patients who underwent their first autologous single (SET) or double frozen embryo transfer (DET) utilizing oral estradiol and resulting in blastocyst transfer from June 1, 2012, to June 30, 2018. Main outcome measures included implantation, clinical pregnancy, live birth, and miscarriage rates. Cycles were stratified by quartile of serum estradiol on the day of progesterone start and separately analyzed for SET cycles only. Poisson and Log binomial regression were used to calculate relative risks (RR) with 95% confidence intervals (CI) for implantation, clinical pregnancy, live birth, and miscarriage with adjustments made for age and BMI. RESULTS: Cycles with the highest quartile of estradiol (mean 528 pg/mL) were associated with lower risks of implantation (RR 0.66, CI 0.50-0.86), ongoing pregnancy (RR 0.66, CI 0.49-0.88), and live birth (RR 0.70, CI 0.52-0.94) compared with those with the lowest estradiol quartile (mean 212 pg/mL). Similar findings were seen for analyses limited to SETs. There was no significant difference in miscarriage rate or endometrial thickness between groups. CONCLUSION: High levels of serum estradiol on the day of progesterone start may be detrimental to implantation, pregnancy, and live birth following frozen blastocyst transfer.

High estradiol level is associated with erectile dysfunction: A systematic review and meta-analysis.

Numerous studies conducted to study the role of testosterone in erectile dysfunction (ED) extensively, but less is known of the association between estradiol level and ED. To assess the strong association between estradiol and ED by quantitatively synthesizing all studies evaluating the relationship between estradiol and ED. An extensive literature search was conducted by two authors independently in three electronic databases, including PubMed, Web of Science and Cochrane Library, up to January 10, 2021. The Patient Population or Problem, Intervention, Comparison, Outcomes and Setting (PICOS) were used for inclusion criteria to identify studies. The Newcastle-Ottawa Scale was applied to assess the quality of studies. The standardized mean difference (SMD) and their corresponding 95% confidence intervals (95% CIs) were used to compare the estradiol level between ED patients and healthy subjects, and the pooled OR and 95%CI were used to evaluate the strong association between estradiol level and ED. Finally, six studies were included in this meta-analysis, satisfying predefined inclusion criteria. Five studies were considered to be high quality, and only one was judged of moderate quality. The estradiol level of ED patients was statistically higher than that in healthy subjects (SMD 0.45, 95%CI 0.28-0.63, p <0.0001). The pooled OR demonstrated that the estradiol was correlated to the ED significantly (OR 1.08, 95%CI 1.05-1.12, p <0.0001). Subgroup analyses were conducted based on age, diagnosis way, country, sample size, detection method and estradiol level. There was no substantial change in the result of SMD ranging from 0.41 (95% CI 0.31-0.51) to 0.53 (95% CI 0.44-0.62) when performing sensitivity analysis. No publication bias was detected by the Begg test or Egger test. This meta-analysis demonstrated that the estradiol level is correlated to ED significantly.

The sex-specific difference in singleton birth weight after frozen embryo transfer compared with fresh embryo transfer: a secondary analysis of 3 randomized trials.

OBJECTIVE: To assess whether the between-group difference in singleton birth weight following frozen vs. fresh embryo transfer varied with infant sex. DESIGN: A post hoc exploratory secondary analysis of data from three multicenter randomized trials compared the live birth rates between freeze-only vs. fresh embryo transfer. SETTING: Academic fertility centers. PATIENT(S): A total of 1,886 women who achieved singleton live birth after a frozen or fresh embryo transfer during these trials were included. INTERVENTION(S): Women underwent either a frozen or fresh embryo transfer. MAIN OUTCOME MEASURE(S): Mean birth weight, large for gestational age (LGA), and small for gestational age (SGA). RESULT(S): There was an interaction between the types of embryo transfer and infant sex on the birth weight and on the incidences of LGA and SGA. Among male infants, compared with singletons following fresh embryo transfer, singletons following frozen embryo transfer had higher mean birth weights (3,520.6 ± 526.1 vs. 3,345.1 ± 524.9 g), a higher risk of being LGA (25.2% vs. 15.7%), and a lower risk of being SGA (3.3% vs. 6.1%). However, among the female infants, no statistically significant difference was found in the mean birth weight (3,336.5 ± 514.8 vs. 3,299.5 ± 485.0 g) or the risks of being LGA (18.8% vs. 15.7%) or SGA (5.2% vs. 6.0%) between frozen and fresh embryo transfer. CONCLUSION(S): Male singletons born after frozen embryo transfer were more likely to have a higher birth weight than those born after fresh embryo transfer.

Clinical and perinatal outcomes of fresh single-blastocyst-transfer cycles under an early follicular phase prolonged protocol according to day of trigger estradiol levels.

BACKGROUD: This study's objectives were to compare the clinical, perinatal, and obstetrical outcomes of patients with different estradiol (E2) levels in fresh single-blastocyst-transfer (SBT) cycles under an early follicular phase prolonged regimen on the day of trigger. METHODS: We recruited patients in fresh SBT cycles (n = 771) undergoing early follicular phase prolonged protocols with ß-hCG values above 10 IU/L between June 2016 and December 2018. Patients who met the inclusion and exclusion criteria were divided into four groups according to their serum E2 level percentages on the day of trigger: <25th, 25th-50th, 51st-75th, and >75th percentile groups. RESULTS: Although the rates of clinical pregnancy (85.57% (166/194)), embryo implantation 86.60% (168/194), ongoing pregnancy (71.13% (138/194)), and live birth (71.13% (138/194)) were lowest in the >75th percentile group, we did not observe any significant differences (all P > 0.05). We used this information to predict the rate of severe ovarian hyperstimulation syndrome (OHSS) area under the curve (AUC) = 72.39%, P = 0.029, cut off value of E2 = 2,893 pg/ml with the 75% sensitivity and 70% specificity. The 51st-75th percentile group had the highest rates of low birth weight infants (11.73% (19/162), P = 0.0408), premature delivery (11.43% (20/175), P = 0.0269), admission to the neonatal intensive care unit (NICU) (10.49% (17/162), P = 0.0029), twin pregnancies (8.57% (15/175), P = 0.0047), and monochorionic diamniotic pregnancies (8.57% (15/175); P = 0.001). We did not observe statistical differences in obstetrics complications, including gestational diabetes mellitus (GDM), gestational hypertension, placenta previa, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM). CONCLUSION: We concluded that serum E2 levels on the day of trigger were not good predictors of live birth rate or perinatal and obstetrical outcomes. However, we found that high E2 levels may not be conducive to persistent pregnancies. The E2 level on the day of trigger can still be used to predict the incidence of early onset severe OHSS in the fresh SBT cycle.

SERUM HORMONE CONCENTRATIONS IN TRANSGENDER INDIVIDUALS RECEIVING GENDER-AFFIRMING HORMONE THERAPY: A LONGITUDINAL RETROSPECTIVE COHORT STUDY.

OBJECTIVE: To examine the association of various gender-affirming hormone therapy regimens with blood sex hormone concentrations in transgender individuals. METHODS: This retrospective study included transgender people receiving gender-affirming hormone therapy between January 2000 and September 2018. Data on patient demographics, laboratory values, and hormone dose and frequency were collected. Nonparametric tests and linear regression analyses were used to identify factors associated with serum hormone concentrations. RESULTS: Overall, 196 subjects (134 transgender women and 62 transgender men), with a total of 941 clinical visits, were included in this study. Transgender men receiving transdermal testosterone had a significantly lower median concentration of serum total testosterone when compared with those receiving injectable preparations (326.0 ng/dL vs 524.5 ng/dL, respectively, P = .018). Serum total estradiol concentrations in the transgender women were higher in those receiving intramuscular estrogen compared with those receiving oral and transdermal estrogen (366.0 pg/mL vs 102.0 pg/mL vs 70.8 pg/mL, respectively, P < .001). A dose-dependent increase in the hormone levels was observed for oral estradiol (P < .001) and injectable testosterone (P = .018) but not for intramuscular and transdermal estradiol. Older age and a history of gonadectomy in both the transgender men and women were associated with significantly higher concentrations of serum gender-affirming sex hormones. CONCLUSION: In the transgender men, all routes and formulations of testosterone appeared to be equally effective in achieving concentrations in the male range. The intramuscular injections of estradiol resulted in the highest serum concentrations of estradiol, whereas transdermal estradiol resulted in the lowest concentration. There was positive relationship between both oral estradiol and injectable testosterone dose and serum sex hormone concentrations in transgender people receiving GAHT.

Determinants of attained estradiol levels in response to oral estradiol plus progesterone therapy.

OBJECTIVES: Among postmenopausal women taking hormone therapy (HT), the estradiol (E2) dose and E2 levels were differentially associated with change in metabolic measures. We evaluated determinants of attained E2 levels in response to HT. METHODS: Postmenopausal women from the REPLENISH trial tested four formulations of oral combined E2 and progesterone compared with placebo. Mixed-effects linear models assessed characteristics associated with E2 levels among women with ≥80% HT compliance, adjusted for E2 dose and baseline E2 level. RESULTS: Among 1173 postmenopausal women with mean (standard deviation) age 55 (4.3) years and 5.2 (4.8) years since menopause, higher treated E2 levels were significantly related to younger age, more recent menopause, and current alcohol use, while lower E2 levels were related to current smoking. Both age and time since menopause were significantly inversely associated with E2 levels; time since menopause had a stronger association with E2 levels. In the final multivariable model, E2 levels were positively associated with current alcohol use, and inversely associated with time since menopause and current smoking. CONCLUSION: Adjusting for E2 dose and baseline E2 level, on-trial E2 levels were significantly associated with time since menopause, current smoking, and current alcohol use. Practitioners should consider these factors in individual women to achieve a desirable E2 level during HT.

The Determination of Estradiol to Cumulus Oocyte Complex (COC) Number Ratio: Does it Predict the Outcomes of ART Cycles?

BACKGROUND: The aim of this study was to assess the impact of total serum E2 on the day of human chronic gonadotropin (hCG) administration and the serum E2 per oocyte ratio on the outcomes of assisted reproductive technology (ART) cycles. METHODS: A total of 205 women were categorized into 3 groups according to the serum E2 levels: 1: ≤1500 pg/ml; 2: 1500-3000 pg/ml; 3: >3000 pg/ml. Another categorization included 3 groups according to E2/oocyte ratio: A: ≤150 pg/ml per oocyte; B: 150-200 pg/ml per oocyte; and C: >200 pg/ml per oocyte. The outcome compared between groups included laboratory and clinical characteristics. One-way analysis of variance (ANOVA), chi-square and Kruskal-Wallis, and multiple logistic regression model were performed, and appropriate differences were considered significant at p<0.05. RESULTS: There was a significant difference between the groups based on the E2 levels with respect to laboratory parameters. In group C, the rates of chemical pregnancy (54.1%), clinical pregnancy (50%) and live birth (45.8%) were significantly higher, when compared to other groups. Moreover, according to E2/oocyte ratio, the rate of live birth was higher in group C compared with group A (18.3%, p=0.04), and group C (29.7%, p<0.0001). Logistic regression showed the number of good quality embryos was a positive predictor for live birth (odds ratio=2.03, 95% CI=1-4.1), but the level of E2 on day of HCG was a negative predictor (odds ratio=0.99, 95% CI=0.99-1). CONCLUSION: Supraphysiological levels of E2 had no adverse effects on the quality of the embryos in IVF cycles, but may have adverse effect on live birth in fresh transfer. Also, it is confirmed that both the pregnancy and live birth rates were elevated with E2/oocyte ratio ≥200 pg/ml.

Impact of Supraphysiological Estradiol Serum Levels on Birth Weight in Singletons Born After Fresh Embryo Transfer.

In assisted reproductive technology, high estradiol (E2) levels at trigger may increase the risk of low birth weight (LBW). Our objective was to investigate the impact of supra-physiological E2 levels at trigger, on the rate of LBW in singleton pregnancies following fresh embryo transfers (ET), in a center that typically employs the 'freeze-all' strategy in case of high E2 levels, to prevent ovarian hyper stimulation syndrome risk. A cohort study was conducted in a university hospital between November 2012 and January 2017. The main inclusion criterion was having a live birth (LB) singleton (≥ 24 weeks of gestation) after a fresh-ET. Four groups were defined according to the E2 level at trigger, as quartiles of the entire patient population. The main measured outcome was the rate of LBW. 497 fresh-ET led to LB. Mean E2 level was 1608.4 ± 945.5 pg/ml. The groups were allocated as follows: 124LB in the Group E2 < 25 percentile(p) (1106.5 pg/ml), 124LB in the Group E2 [25p-50p] (1106.5-1439 pg/ml), 124LB in the Group E2[50p-75p] (1440-1915 pg/ml), and 125LB in the Group E2 > 75p (>1915 pg/ml). There was no significant difference in the rate of LBW (Group E2 < 25p, n = 8/124, (6.5%); Group E2[25p-50p], n = 15/124, (12.1%); Group E2 [50p-75p], n = 13/124, (10.4%); and Group E2 > 75p, n = 10/12, (8.1%); (p = 0.43)). After multivariate analysis, E2 level at trigger was not significantly correlated to the rate of LBW. In our cohort, E2 level on the day of hCG trigger was not associated with increased odds of LBW after fresh embryo transfers.

Lifestyle Factors Rather Than Helicobacter pylori Infection or Estradiol Level are Associated With Osteopenia in Japanese Men.

Although decreased calcium absorption, decreased bone formation, alcohol drinking, and smoking have been considered as causes of osteopenia in men, the cause is unknown in half of the cases. Many reports highlighted the association between Helicobacter pylori infection and osteoporosis, mainly in East Asia and Japan. To identify relevant factors of osteoporosis in men, we examined estrogen and calcium intakes and other lifestyle factors together with gastric mucosal atrophy caused by Helicobacter pylori infection. This study is a cross-sectional study design of 268 healthy men who underwent general medical examinations. Multivariate analysis was performed, with age, body mass index, smoking habit, drinking habit, exercise habit, estradiol level, calcium intake, and Helicobacter pylori infection and its associated gastric mucosal atrophy as the independent variables and the presence of osteopenia as the dependent variable. The adjusted odds ratio was 0.74 (95% Confidence Interval [0.29, 1.90], p = .531) and 1.31 (95% Confidence Interval [0.54, 3.21], p = .552), when Helicobacter pylori infection was positive without and with gastric mucosal atrophy, respectively. Helicobacter pylori infection and gastric mucosal atrophy were not significant factors. Low body mass index, smoking habit, and low calcium intake were significantly associated with decreased bone density. In conclusion, Helicobacter pylori infection was not a significant risk, whereas low body mass index, current smoking, and lower calcium intake had a significant influence on the development of osteopenia in men.

Endometrial but not Ovarian Response is Associated With Clinical Outcomes and can be Improved by Prolonged Pituitary Downregulation in Patients With Thin and Medium Endometrium.

The aim of this study is to investigate the effect of ovarian and endometrial response on live birth rates (LBRs) in young normal and high responders and prolonged pituitary downregulation on endometrial receptivity and clinical outcomes in patients with different endometrial thickness. Between January 2013 and December 2017, 9511 patients underwent first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles with age ≤35 years, follicle stimulating hormone < 10 IU/l, and ≥4 retrieved oocytes were conducted. The estradiol (E2) levels on the human chorionic gonadotropin (HCG) day were classified into 4 groups: group 1 (<3000 pg/mL); group 2 (3000-5000 pg/mL); group 3 (5000-7000 pg/mL), and group 4 (≥7000 pg/mL). Logistic regression analysis was performed to predict the independent variables for live birth. Clinical outcomes between gonadotropin-releasing hormone agonist (GnRH-a) long protocol and GnRH-a prolonged protocol in patients with different endometrial thickness (EMT) were compared. There were no significant differences among the 4 groups in implantation rates, clinical pregnancy rates, and LBRs (P > .05). Binary logistic regression analysis suggested that EMT but not E2 levels was one of the independent predictive factors of LBRs (odds ratio 0.889, 95% confidence interval, 0.865-0.914, P < .001). The prolonged protocol had significantly higher implantation rates and clinical pregnancy rates in patients with medium (7 < EMT < 14 mm), especially thin endometrium (≤7 mm) compared to short GnRH-a long protocol. Our study showed that endometrial response but not ovarian response was associated with LBRs in young normal and hyper responders. Prolonged pituitary downregulation was an effective treatment to improve endometrial receptivity in patients with medium, especially thin endometrium.

The association between estradiol levels and cognitive function in postmenopausal women.

BACKGROUND: Levels of estradiol decreases as women arrive the menopausal transition and enter to a low, steady level during the early postmenopause. In addition, memory dysfunction are highly prevalent during this period. OBJECTIVE: Our study was designed to determine whether endogenous levels of estradiol are related to cognitive function in postmenopausal. MATERIALS AND METHODS: The cross-sectional study was conducted between November 2015 to February 2016 on 209 healthy postmenopausal women. The women filled out the Montreal Cognitive Assessment (MoCA) scale. Then, estradiol level was tested for association with cognitive function adjusted for factors supposed to confound this association. RESULTS: The prevalence of cognitive dysfunction; MoCA points ≤26 in our participants was 62.7%, and mean±SD of estradiol level was 14.92±10.24pg/ml in participants with cognitive dysfunction in comparison with 21.67±14.92pg/ml in those with normal cognitive function (p<0.001). There were significant association between MoCA points with estradiol level (p<0.001) and educational status (p<0.001). CONCLUSION: Estradiol replacement therapy in postmenopausal women with low endogenous estradiol levels and decreased cognitive function might be necessary.

Mild ovarian stimulation with letrozole plus fixed dose human menopausal gonadotropin prior to IVF/ICSI for infertile non-obese women with polycystic ovarian syndrome being pre-treated with metformin: a pilot study.

BACKGROUND: Letrozole is widely employed as ovulation induction agent in women with PCOS, but its use in mild stimulation (MS) protocols for IVF is limited. Aim of the present study was to evaluate the feasibility of a MS protocol with letrozole plus hMG in non-obese PCOS women undergoing IVF after a metformin pre-treatment. METHODS: We retrospectively evaluated the data of 125 non-obese PCOS undergoing MS with letrozole plus hMG, 150 IU as starting dose, (group 1, N = 80) compared to those undergoing a conventional IVF stimulation protocols (CS) (group 2, N = 45) prior to IVF. All patients had received metformin extended release 1200-2000 mg daily for three to six months before IVF. GnRH antagonist was administered in both groups when the leading follicles reached 14 mm. RESULTS: Both groups were comparable for age, BMI and ovarian reserve markers. Both groups showed lower than expected AFC and AMH values as a consequence of metformin pre-treatment. Letrozole-treated patients required a significantly lower amount of gonadotropins units (p < 0.0001), and showed significantly lower day 5, day 8 and hCG day E2 levels compared to patients undergoing the CS protocol (p < 0.0001, p < 0.0001 and p = 0.001 respectively). The oocyte yield, in terms of total (6, IQR 3, vs 6, IQR 4 respectively,) and MII oocytes (5, IQR 3, vs 5, IQR 3, respectively) number, did not differ among groups; the number of total (3, IQR 2, vs 3, IQR 1 respectively) and good quality embryos (2, IQR1 vs 2, IQR 1,5 respectively) obtained was comparable as well in the two groups. The number of fresh transfers was significantly higher in group 1 compared to group 2 (80% vs 60%, p = 0.016). A trend for higher cumulative clinical pregnancy rate was found in women undergoing MS compared to CS (42.5%vs 24,4%, p = 0.044), but the study was not powered to detect this difference. CONCLUSIONS: The present study suggests that the use of letrozole as adjuvant treatment to MS protocols for IVF may be an effective alternative to CS protocols for non-obese PCOS patients pre-treated with metformin, as it provides comparable IVF outcome without requiring high FSH dose, and avoiding supraphysiological estradiol levels.

The effect of premature luteinizing hormone increases among high ovarian responders undergoing a gonadotropin-releasing hormone antagonist ovarian stimulation protocol.

OBJECTIVE: To explore factors causing a premature rise in luteinizing hormone among high ovarian responders undergoing the gonadotropin-releasing hormone (GnRH) antagonist ovarian stimulation protocol. METHODS: The present retrospective study included healthy women undergoing fresh cycles using a fixed GnRH antagonist protocol with a predicted high response and antral follicle count (AFC) of at least 15 at the Reproductive Medicine Center of Tongji Hospital, China, between January 1 and December 31, 2016. Treatment-related characteristics, hormone changes, and pregnancy outcomes were compared between patients who did or did not experience a premature luteinizing hormone rise. RESULTS: There were 314 patients included; 49 experienced premature luteinizing hormone increases. Among patients who experienced a premature rise in luteinizing hormone, a lower two pronuclear embryo rate (P=0.038); fewer high-quality embryos (P=0.020); higher serum luteinizing hormone (P=0.006), progesterone (P=0.013), and estradiol (E2) levels (P=0.003) on the day of human chorionic gonadotropin administration; a lower clinical pregnancy rate (P=0.031); and a higher cancellation rate (P=0.006) were observed. AFC of at least 22 (P=0.001) and E2 of 669 pg/mL or higher at the start of GnRH antagonist administration were predictive of early (P=0.036) and late (P=0.033) premature luteinizing hormone increases. CONCLUSION: Earlier administration of GnRH antagonist could avoid premature luteinizing hormone increases among high ovarian responders, especially those with a starting AFC of 22 or more.

Maternal high estradiol exposure alters CDKN1C and IGF2 expression in human placenta.

INTRODUCTION: The increased maternal estradiol (E2) concentrations induced by assisted reproductive technology (ART) result in lower birth weight of offspring, which is associated with increased risk of adult diseases. However, the exact mechanism remains unknown. The present study investigated the effect of high E2 exposure on the expression of imprinted genes CDKN1C and IGF2 in human placentas and the DNA methylation status of their differential methylation regions (DMRs). METHODS: The mRNA expression of CDKN1C and IGF2 in human placentas and the human trophoblast cells (HTR8) treated with E2 were investigated by reverse transcription-real time polymerase chain reaction (PCR). The DNA methylation of their DMRs were investigated by sodium bisulfite sequencing. RESULTS: CDKN1C and IGF2 were significantly up-regulated in ART conceived placentas. The mean birth weight of ART singletons was significantly lower than that of naturally conceived (NC) ones, with the increased percentage of small-for-gestational-age (SGA) birth. The DNA methylation was significantly down-regulated in the DMR of CDKN1C (KvDMR1) and up-regulated in the DMR of IGF2 (H19 DMR) in ART placentas. The treatment of E2 altered the expression of the two genes and the DNA methylation of their DMRs in HTR8 to a similar tendency as in vivo. DISCUSSION: The maternal high E2 levels after ART up-regulate the expression of imprinted genes in human placentas through epigenetic modifications, which influences the growth potential of the offspring. Further studies are needed to follow up the growth and development of the ART offspring.

How low is too low? Cycle day 28 estradiol levels and pregnancy outcomes.

OBJECTIVE: To determine the utility of cycle day 28 estradiol (E2) levels in predicting pregnancy outcomes after IVF. DESIGN: Retrospective, cohort study. SETTING: Academic medical center. PATIENT(S): All IVF cycles resulting in a positive pregnancy test result at our center between January 2007 and December 2012 were included. INTERVENTION(S): In vitro fertilization with fresh embryo transfer. MAIN OUTCOME MEASURE(S): A total of 5,471 IVF cycles were identified. Cycles were stratified by day-28 E2 level (pg/mL) into three groups: A: ≤50; B: 51-100; and C: >100. Outcomes measured were live birth, clinical pregnancy, biochemical, ectopic, and spontaneous abortion rates. RESULT(S): There were 806, 588, and 4,077 IVF pregnancies in groups A, B, and C, respectively. Live birth rates were lower in groups A (15.4%) and B (41.2%) compared with group C (77.4%), representing decreased odds of live birth in patients with E2 levels of ≤50 pg/mL (odd ratio 0.05, 95% confidence interval 0.04-0.07) and in patients with levels of 51-100 pg/mL (odds ratio 0.20, 95% confidence interval 0.17-0.25) compared with patients with levels >100 pg/mL. Rates of biochemical and ectopic pregnancies were higher in groups A (66.5%, 6.20%) and B (30.7%, 3.57%) compared with group C (7.31%, 0.66%). An hCG level <50 mIU/mL was associated with increased odds of a biochemical pregnancy and decreased odds of a live birth. CONCLUSION(S): Low E2 levels early in IVF pregnancies are associated with poorer pregnancy outcomes. Estradiol can be used alone or in conjunction with hCG levels to predict the odds of a live birth.

The predictive value of serum estradiol level during early phase of controlled ovarian hyperstimulation in IVF-ET / 实用医学杂志

Objective To evaluate the value of serum E2 levels during COH in predicting IVF-ET outcome. Method Data from 311 IVF-ET cycles received long protocol were collected and analyzed according to E 2 levels 5 days after stimulation:Group A (E2≤500 pmol/L), Group B (500 2 000 pmol/L). Results In groups with E2>1 000 pmol/L, the conditions of oocyte and embryo are higher than E2 2 000 pmol/L, the pregnancy rate become lowest. Conclusion E2 levels among 1 000~1 500 pmol/L during early COH predicts a better pregnancy outcome.