Day-3 FSH Research Articles

The impact of cryopreserved sperm on intrauterine insemination outcomes: is frozen as good as fresh?

Frozen sperm utilization might negatively impact cycle outcomes in animals, implicating cryopreservation-induced sperm damage. However, in vitro fertilization and intrauterine insemination (IUI) in human studies are inconclusive. This study is a retrospective review of 5,335 IUI [± ovarian stimulation (OS)] cycles from a large academic fertility center. Cycles were stratified based on the utilization of frozen (FROZEN, n = 1,871) instead of fresh ejaculated sperm (FRESH, n = 3,464). Main outcomes included human chorionic gonadotropin (HCG) positivity, clinical pregnancy (CP), and spontaneous abortion (SAB) rates. Secondary outcome was live birth (LB) rate. Odds ratios (OR) for all outcomes were calculated utilizing logistic regression and adjusted (adjOR) for maternal age, day-3 FSH, and OS regimen. Stratified analysis was performed based on OS subtype [gonadotropins; oral medications (OM): clomiphene citrate and letrozole; and unstimulated/natural]. Time to pregnancy and cumulative pregnancy rates were also calculated. Further subanalyses were performed limited to either the first cycle only or to the partner's sperm only, after excluding female factor infertility, and after stratification by female age (<30, 30-35, and >35 years old). Overall, HCG positivity and CP were lower in the FROZEN compared to the FRESH group (12.2% vs. 15.6%, p < 0.001; 9.4% vs. 13.0%, p < 0.001, respectively), which persisted only among OM cycles after stratification (9.9% vs. 14.2% HCG positivity, p = 0.030; 8.1% vs. 11.8% CP, p = 0.041). Among all cycles, adjOR (95% CI) for HCG positivity and CP were 0.75 (0.56-1.02) and 0.77 (0.57-1.03), respectively, ref: FRESH. In OM cycles, adjOR (95% CI) for HCG positivity [0.55 (0.30-0.99)] and CP [0.49 (0.25-0.95), ref.: FRESH] favored the FRESH group but showed no differences among gonadotropin and natural cycles. SAB odds did not differ between groups among OM and natural cycles but were lower in the FROZEN group among gonadotropin cycles [adjOR (95% CI): 0.13 (0.02-0.98), ref.: FRESH]. There were no differences in CP and SAB in the performed subanalyses (limited to first cycles or partner's sperm only, after excluding female factors, or after stratification according to female age). Nevertheless, time to conception was slightly longer in the FROZEN compared to the FRESH group (3.84 vs. 2.58 cycles, p < 0.001). No significant differences were present in LB and cumulative pregnancy results, other than in the subgroup of natural cycles, where higher LB odds [adjOR (95% CI): 1.08 (1.05-1.12)] and higher cumulative pregnancy rate (34% vs. 15%, p = 0.002) were noted in the FROZEN compared to the FRESH group. Overall, clinical outcomes did not differ significantly between frozen and fresh sperm IUI cycles, although specific subgroups might benefit from fresh sperm utilization.

Perceived stress and markers of ovarian reserve among subfertile women

Research questionIs self-reported psychological stress associated with markers of ovarian reserve among subfertile women? DesignObservational study of women (n = 520) seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health study between 2005 and 2019. Women completed the short version of the validated PSS4, which assesses psychological stress. Ovarian reserve markers included AFC and circulating serum levels of day-3 FSH, with AMH assessed in a subset of participants (n = 185). ResultsHigher total PSS4 scores were negatively associated with AFC and serum AMH levels. Analyses adjusted for age, BMI, race, smoking, education, physical activity and type of infertility diagnosis. Women in the second and third tertiles of stress had lower AFC (13.3, 95% CI 12.7 to 13.8; and 13.5, 95% CI 13.0 to 14.1) compared with women in the lowest tertile of psychological stress score (14.3, 95% CI 13.8 to 14.9, both P < 0.05). Women in the second and third tertiles of total PSS4 scores also had lower mean serum AMH compared with women in the lowest tertile (2.99, 95% CI 2.24 to 3.74), and (2.99 95% CI 2.22 to 3.76) versus (3.94 95% CI 3.23 to 4.64). These associations varied by several socioeconomic factors, and were observed among women who were younger, belonging to minority races, with a college degree or with annual household income less than $100,000. ConclusionsHigher perceived stress was negatively associated with AFC and serum AMH levels. These associations varied by several socioeconomic factors.

O-299 Analyzing the impact of simple wash versus density gradient sperm preparations on intrauterine insemination outcomes. Is the cost-effective and time-efficient option just as good?

Abstract Study question How do different sperm preparations, such as simple-wash (SW) and density-gradient (DG), impact intrauterine insemination (IUI) outcomes among women seeking fertility treatments? Summary answer Using a population from a large, academic medical center, this study discerned no differences in pregnancy outcomes between SW and DG sperm preparations. What is known already IUI with or without ovulation induction (OI) is often a first-line treatment among couples seeking fertility services. SW and DG are two common methods used to prepare sperm for IUI. In comparison to its latter counterpart, the SW technique is lesser-used, yet is more time-efficient, and cost-effective due to its utilization of only a single centrifugation step. Since the impact of sperm preparation techniques on the post-processing sperm yield and its parameters varies by the method used, the cycle outcomes might differ as well. However, limited data exists on various sperm preparations’ impact on IUI clinical outcomes. Study design, size, duration Data from 3378 IUI+OI cycles (from 1503 women of all diagnoses seeking IUI with fresh-ejaculated sperm) that took place at a large academic fertility center between 9/2014 and 3/2021 were retrospectively reviewed. Cycles were either unstimulated (natural) or stimulated with either oral OI agents (clomiphene-citrate &amp; letrozole) or gonadotropins. Cycles were divided in two groups based on sperm preparation technique: SW (n = 1691) and DG (n = 1687) and outcomes were compared between them. Participants/materials, setting, methods Sperm preparation: SW semen were mixed in 10ml MHM (FujiFilm) and centrifuged for 10min. DG semen were layered over 45:90 gradient of Isolate (FujiFilm), centrifuged for 20min, and washed twice (10min) in 10ml MHM. Outcome measures: hCG-positivity (posHCGR), clinical pregnancy (CPR), spontaneous abortion (SABR), and livebirth rates/cycle (LBR). Statistics: Logistic regression with Odds Ratios (OR) adjusted for both partners’ ages, day-3 FSH, stimulation, and sperm score (poor, fair, good, excellent). Sub-analysis limited cohort to first-cycles only. Main results and the role of chance Groups were comparable in patient [age (maternal, paternal), BMI, day-3 FSH, infertility diagnosis], and cycle characteristics [follicular response (measured as number of preovulatory follicles), and endometrial thickness]. Preprocessing sperm parameters differed slightly with higher mean sperm concentrations and lower total motility among SW cycles (75.3 + 57.0 vs. 71.0 + 51.3 million, p = 0.02; 48.6 + 19.6 vs. 52.5 + 20.2, p &amp;lt; 0.001, for SW and DG, respectively). posHCGR, CPR, SABR, and LBR per cycle did not differ between groups (15.8% vs. 15.4%, p = 0.76;13.7% vs. 13.2%, p = 0.62;18.1% vs. 18.5%, p = 0.93; 9.5 vs. 8.9%, p = 0.56; for SW and DG, respectively). Odds for posHCG, CP, SAB, or LB did not differ between groups [adjOR(95%CI): 1.05(0.87-1.26), p = 0.65; 1.10(0.67-1.83), p = 0.71; 0.98(0.60-1.60), p = 0.94; 1.08(0.85-1.37), p = 0.66, respectively]. When cycles were stratified by type of ovarian stimulation, rather than adjusted for it, no difference was seen in any of the clinical outcomes within individual strata{adjOR(95%CI): [Oral OI: 1.00(0.74-1.37), p = 0.98; 1.78(0.68-4.61), p = 0.25; 0.97(0.40-2.38), p = 0.95; 1.05(0.72-1.53), p = 0.81], [Gonadotropins: 0.99(0.78-1.28), p = 0.96; 0.93(0.49-1.77), p = 0.83; 0.97(0.52-1.80), p = 0.96; 1.03(0.75-1.41), p = 0.87], [Natural: 2.36(0.97-5.76), p = 0.06; 0.08(0.001-6.84), p = 0.26; 0.20(0.003-11.02), p = 0.43; 2.52(0.63-10.00), p = 0.19], for posHCG, CP, SAB, and LB, respectively}. Similarly, no difference was seen in any of the clinical outcomes when cycles were stratified by sperm score or when analysis was limited to first-cycles only. Limitations, reasons for caution LBR were calculated excluding pregnancies with no information after discharge to obstetrics (approximately 16%). Although not significant, there might be minor variations in individual provider’s practices between time frames in which these techniques were implemented. Wider implications of the findings SW is a much simpler, time-efficient, and cost-effective sperm processing technique for IUI compared to DG, however remains infrequently utilized. Adoption of SW, over DG, could yield comparable clinical efficacy, yet optimize teamwork flow and lower healthcare costs, due to its non-labor-intensive and inexpensive nature. Trial registration number not applicable

O-184 The impact of cryopreserved sperm on Intrauterine Insemination (IUI) outcomes: Is frozen as good as fresh?

Abstract Study question Are the outcomes of IUI cycles [with or without ovarian stimulation (OS)] comparable when frozen instead of fresh-ejaculated sperm is utilized? Summary answer Overall, clinical outcomes did not differ significantly between frozen and fresh sperm IUI cycles, although specific subgroups might benefit from fresh sperm utilization. What is known already At present, data from animal studies point towards less favorable outcomes with frozen sperm utilization, implicating cryopreservation-induced damages to the cytoskeleton, DNA, and acrosome leading to adverse effects on spermatozoa’s motility, viability, and ability to fuse with the oocyte. Assisted Reproductive Technology (ART) data, mostly focusing on severe male factor infertility diagnoses, suggest no major differences between in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles utilizing frozen over fresh sperm, often surgically extracted. Nevertheless, contemporary data from IUI(±OS) cycles are still scarce. Study design, size, duration Data from 5335 IUI(±OS) cycles (time-period: 01/2004-12/2021) from a large academic fertility center were retrospectively reviewed. Cycles were stratified in two groups based on utilization of frozen instead of fresh-ejaculated sperm for the IUI [FROZEN (n = 1871, all infertility diagnoses), and FRESH (n = 3464, idiopathic infertility diagnosis only), respectively]. Cycle outcomes were compared between groups. Participants/materials, setting, methods Participants: women seeking IUI (±OS) treatments. Outcome Measures: HCG-positivity, clinical pregnancy (CP), spontaneous abortion (SAB) rates. Initial analysis included all cycles irrespective of OS regimen. Cycles were then stratified by OS regimen into three subgroups [injectable gonadotropins, oral medications (OM): clomiphene-citrate and letrozole, and unstimulated/natural]. Odds ratios (OR) for all relevant outcomes were calculated utilizing logistic regression and adjusted for maternal age, day-3 FSH, and OS regimen. Time-to-pregnancy and first-cycle only analyses were also performed. Main results and the role of chance Unadjusted HCG-positivity, and CP were lower in the FROZEN compared to the FRESH group (12.2% vs. 15.6%, p &amp;lt; 0.001; 9.4% vs. 13.0%, p&amp;lt;.001, respectively), which persisted only among OM after stratification (9.9% vs. 14.2% HCG-positivity, p=.030; 8.1% vs. 11.8% CPR, p=.041, for FROZEN compared to FRESH, respectively). Among all cycles, adjOR(95%CI) for HCG-positivity and CP were respectively: 0.75(0.56-1.02), and 0.77(0.57-1.03), ref: FRESH). Following stratification by OS regimen, adjOR(95%CI) for HCG-positivity and CP showed no difference between groups among gonadotropin and natural cycles but favored the FRESH group in OM cycles [HCG-positivity: 0.55(0.30-0.99); CP: 0.49(0.25-0.95), ref.: FRESH]. SAB odds did not differ between groups among OM and natural cycles but were lower in the FROZEN compared to FRESH group among gonadotropin cycles [adjOR(95%CI): 0.13(0.02-0.98), ref.: FRESH]. However, regarding the latter comparison, numbers were small and the 95%CI wide. When analysis was limited to first-cycles only and further stratified by OS regimen, the previously noted differences in CP and SAB odds no longer existed within the OS subgroups. Nevetheless, time-to-conception was slightly longer in the FROZEN compared to the FRESH group (3.84 vs. 2.58 cycles, p&amp;lt;.001). Limitations, reasons for caution Study is limited by its retrospective nature. The two groups differed somewhat in age, infertility diagnosis, utilized OS regimen, and as expected in total motile sperm counts. Despite the less favorable characteristics of the FROZEN group, no detrimental effect of sperm cryopreservation on IUI outcomes was noted. Wider implications of the findings Our study, the largest to date, showed no significant difference in IUI outcomes between cycles utilizing frozen instead of fresh-ejaculated sperm. Although, specific subgroups might benefit from fresh sperm utilization and time-to-pregnancy might be shorter with fresh over frozen sperm, patients should be counselled about the non-inferiority of frozen sperm. Trial registration number Not applicable

Trapa bispinosa Roxb. extract lowers advanced glycation end-products and increases live births in older patients with assisted reproductive technology: a randomized controlled trial

BackgroundAdvanced glycation end-products (AGE), which accumulate with insulin resistance and aging, impair folliculogenesis and may decrease endometrial receptivity. Hishi (Trapa bispinosa Roxb.) extract, a safe herbal medicine, strongly inhibits AGE formation in vitro. We determined whether Hishi lowers AGE and increases live births in older assisted reproductive technology (ART) patients.MethodsThis prospective randomized open-label controlled trial included 64 patients 38 to 42 years old undergoing ART with or without Hishi extract between June 11, 2015 and July 12, 2019. None had over 2 ART failures, diabetes, uterine anomalies, or exhausted ovarian reserve. After allocation, the Hishi group received Hishi extract (100 mg/day) until late pregnancy or failure. The control group received no extract. Both groups underwent 1 cycle of conventional infertility treatment; 1 long-protocol cycle of ovarian stimulation, oocyte retrieval, in vitro fertilization/intracytoplasmic sperm injection, and fresh embryo transfer (ET); and, if needed, cryopreserved ET until live birth or embryo depletion. Serum AGE were measured before and during ART, as were AGE in follicular fluid (FF).ResultsCumulative live birth rate among 32 Hishi patients was 47%, significantly higher than 16% among 31 controls (p<0.01; RR, 4.6; 95% CI, 1.4 – 15.0; 1 control dropped out). Live birth rate per ET, including fresh and cryopreserved, was significantly higher with Hishi (28% in 47 ET vs. 10% in 49 ET; p<0.05; RR, 3.4; 95% CI, 1.1-10.4). Among variables including age, day-3 FSH, anti-Müllerian hormone, and Hishi, logistic regression identified only Hishi as significantly associated with increased cumulative live birth (p<0.05; OR, 5.1; 95% CI, 1.4 - 18.3). Hishi significantly enhanced oocyte developmental potential, improved endometrial receptivity in natural cycles, and decreased AGE in serum and FF. Larger serum AGE decreases with Hishi were associated with more oocytes becoming day-2 embryos.ConclusionsHishi decreased AGE in serum and FF and improved oocyte developmental potential and endometrial receptivity, increasing live births in older patients. Treatment of infertility by AGE reduction represents a new addition to infertility treatment. Therapeutic trials of Hishi for other AGE-associated diseases might be considered.Trial registrationUMIN registration in Japan (UMIN000017758) on June 1, 2015. https://www.umin.ac.jp/ctr/index.htm

OVULATION INDUCTION AND INTRAUTERINE INSEMINATION FOR TUBAL FACTOR INFERTILITY: TO DO OR NOT TO DO?

Ovulation induction (OI)/intrauterine insemination (IUI) is an option available to patients with tubal factor infertility (TFI) and one patent fallopian tube. However, patients with a unilateral blocked fallopian tube likely have inherent risk factors for non-viable pregnancies such as ectopic pregnancy1,2. If a patient has an inherent risk factor such as TFI, is IUI a worthwhile treatment, or is it putting the patient at increased risk of ectopic pregnancy? Objective To evaluate the success of OI/IUI (with either oral agents or gonadotropins) in patients with TFI and at least one patent fallopian tube. Design: Retrospective chart review Setting: Large academic fertility center Patients: Women with TFI undergoing OI/IUI from 12/2003 to 09/2019. Interventions: Data from 3555 cycles were retrospectively reviewed. Women with TFI (n=244) were compared to those with idiopathic infertility (IdI) (n =3311). A sub-analysis restricted only to cycles utilizing injectable gonadotropins was also performed, Outcome Measures: Primary: Clinical pregnancy rate (CPR)/cycle, defined as at least one gestational sac identified on transvaginal ultrasound and including viable pregnancies and spontaneous abortions. Secondary: Non-viable pregnancy rate (NVPR), defined as ectopic, biochemical, and pregnancies of unknown location. Statistics: T-tests and x2 were used, as appropriate. Odds ratios were calculated utilizing logistic regression analysis and adjusting for age and BMI. Women with TFI did not differ from those with IdI in regards to age, day-3 FSH, or AMH. TFI/IUI when compared to IdI/IUI cycles, resulted in significantly lower CPR/cycle (8.6% vs. 13.4%, p<0.01, respectively). The unadjusted odds for achieving clinical pregnancy were 40% lower in TFI/IUI compared to IdI/IUI cycles (OR (95%CI): 0.61 [0.38-0.96], p<0.05, for TFI/IUI vs. IdI/IUI). Results did not change when adjusting for maternal age and BMI (adjOR (95%CI): 0.61 [0.38-0.96], p<0.05). NVPRs were comparable between the two groups (16% vs 10.8%, respectfully, adjOR (95%CI): 1.08 [0.87-1.35]). However, as expected, when TFI/IUI cycles were compared to IdI ones, the odds for an ectopic pregnancy were 62% higher (12.0% vs 1.2%, respectfully, aOR [95%CI]:1.62 [1.20-2.19], p<0.01). When analysis was restricted to gonadotropin/IUI cycles (79.5% of TFI/IUI and 62.7% of IdI/IUI cycles) results were similar but differences in CPR were attenuated (10.3% vs 14.7%, p=0.08). No significant difference was found regarding CPR, NVPR or ectopic rate between the TFI/IUI and IdI/IUI groups (Table 1). TFI/IUI cycles that used oral pills for OI had limited cases for statistical comparison with IdI/IUI cyclesTable 1Comparison of TFI/IUI to IdI/IUI Pregnancy OutcomesTubal Factor Infertility/IUI (TFI/IUI)Idiopathic Infertility/IUI (IdI/IUI)Adjusted Odds Ratio OR (CI)All IUIsAll cycles (TFI/IUI n=244, IdI/IUI n=3311)CPR N (%)*21 (8.6)444 (13.4)0.61 (0.38-0.96)*465 (13.1)NVPR N (%)4 (16.0)54 (10.8)1.08 (0.866-1.351)58 (11.1)Ectopic**3 (12.0)6 (1.2)1.62 (1.20-2.19)**9 (1.7)Gonadotropin OI Cycles Only (TFI/IUI n=194, IdI/IUI n=2077)CPR20 (10.3)306 (14.7)0.67 (0.41-1.09)326 (14.4)NVPR1 (4.3)31 (9.1)0.86 (0.57-1.28)32 (8.8)Ectopic1 (4.3)3 (0.9)1.44(0.89-2.34)4 (1.1)*P<0.05, **P<0.01 Open table in a new tab *P<0.05, **P<0.01 Overall, IUI as management for a patient with a unilateral tubal disease leads to a lower chance of clinical pregnancy and higher chance of ectopic pregnancy when compared to patients with idiopathic infertility. The differences in clinical pregnancy rate are attenuated when utilizing gonadotropins for ovulation induction. These patients might benefit from immediate access to ART, instead.

Can anti-müllerian hormone (AMH) predict the outcome of gonadotropin induction/intrauterine insemination (GN/IUI) cycles among infertile women?

To evaluate the ability of AMH to predict treatment outcomes among infertile women undergoing Gn/IUI, given emerging evidence suggesting otherwise among women of normal fertility[1]. Retrospective cohort study. Sample size/Intervention: 1110 Gn/IUI cycles (from 503 women) at a large academic center were analyzed (11/2007-10/2017). Cycles were stratified by AMH serum concentration cutoffs, based on previously published literature: low (<0.7 ng/ml, n=273) and normal (≥0.7 ng/ml, n=837). Outcomes measures: Cumulative probability of achieving i) positive pregnancy test (PPr) and ii) clinical pregnancy (CPr) over a maximum of 4 completed cycles per attempt. Statistics: Pearson’s χ2, t-test, or nonparametric tests were used as appropriate. Cumulative probabilities of achieving the outcomes of interest were determined via the Kaplan-Meier failure function. Cox proportional hazard models (adjusted for age and BMI) were used to determine fecundability ratios (FR) for each AMH group. P <0.05 was considered significant. As expected, mean (SD) age, day-3 FSH, total gonadotropin dose, and duration of stimulation were different between groups: 37.5 (3.8) vs. 35.3 (3.9) years, p<0.01; 10.2 (5.1) vs. 7.0 (2.3) IU/L, p<0.01; 1836.5 (1541.1) vs. 750.8 (582.2) IU, p<0.01; and 10.2 (2.5) vs. 12.2 (4.4) days, p<0.01, for low vs. normal AMH groups, respectively. Conversely, BMI (25.3 [5.1] vs. 24.1 [5.1] kg/m2, p=0.17) and peak estradiol (508.1 [237.6] vs. 462.5 [286.4] pg/ml, p=0.15) did not differ significantly. Women with AMH >0.7 ng/ml were more likely to have either a PPr or CPr with an unadjusted cumulative probability (95%CI) of 31.4% (20.4-46.4) vs. 46.3% (37.4-56.3), p<.005, and 19.9% (11.6-32.7) vs. 29.3% (21.9-38.3), p=0.017, for low vs. normal AMH groups, respectively. Following the same trend, the estimated adjusted FRs revealed that women with AMH >0.7 ng/ml were more likely to have a PPr (adjusted FR: 1.52, 95%CI:0.99-2.35) and CPr (adjusted FR: 1.47, 95%CI:0.92-2.35). Similarly, when further stratified to low (<0.7 ng/ml), normal (0.7-8.4 ng/ml) and high (≥8.5 ng/ml) AMH groups, women with AMH ≥8.5 ng/ml were more likely to have a PPr (adjusted FR: 1.90, 95%CI:1.09-3.28) and CPr (adjusted FR: 1.76, 95%CI: 0.96-3.20) when compared to women with AMH <0.7 ng/ml. Despite the recent evidence that low AMH in a population of fertile women was not associated with reduced fecundability, our findings suggest that among infertile women undergoing Gn/IUI cycles, lower AMH might be associated with lower probability of a successful treatment outcome.

The effect of follicular phase length on endometrial development and the outcomes of ovulation induction/intrauterine insemination (OI/IUI) cycles

Few, limited studies have reported that in IUI cycles a shorter follicular phase is associated with poorer pregnancy outcomes compared to a longer follicular phase [1,2]. However, these studies have been limited by small sample sizes and inadequate control of potential confounders. To evaluate the effect, if any, of follicular phase length on endometrial development and cycle outcomes among patients undergoing OI/IUI. Design: Retrospective cohort study Intervention: Data from 3404 IUI cycles derived from 1502 patients in which gonadotropins were used for OI were analyzed and stratified by follicular phase length (hCG trigger day ≤8 vs. >8). Outcome Measures: Primary outcomes included clinical pregnancy, multiple pregnancy, spontaneous abortion, and non-clinical pregnancy (ectopic/biochemical) rates (CPR, SABR, MPR, and non-CPR, respectively). A secondary outcome was endometrial thickness prior to hCG trigger. Statistics: Demographic factor comparisons between follicular phase length groups were analyzed with Student t-tests, Mann Whitney U-tests, and χ2- tests, as appropriate. Multilevel random and fixed effects regression models were used to calculate odds ratios (ORs) for pregnancy outcomes and regression coefficients for endometrial thickness first by comparing the follicular phase length groups (≤8 vs. >8 days), then by analyzing follicular phase length as a continuous variable. All models adjusted for potential confounders (age, BMI, day-3 FSH) determined a priori. Demographic and cycle characteristics of the study population, stratified by follicular phase length, are outlined in Table 1. After adjusting for potential confounders, cycles with a longer compared to those with a shorter follicular phase resulted in significantly higher CPR (14.0 vs. 9.0%, p = 0.02; respectively). The odds for clinical pregnancy (CP) were 38% higher in the former compared to the latter group, with the difference nearing significance (OR: 1.38, 95%CI: 0.96-1.99, p = 0.082). When follicular phase length was analyzed as a continuous variable, the odds of CP increased by 6.0% (95%CI: 3.0-10.0, p = 0.001) with each additional follicular phase day. Cycles with a longer compared to those with a shorter follicular phase had comparable SABR (21.0 vs. 17.0%, p = 0.54), MPR (11.0 vs. 9.0%, p = 0.58), and non-CPR (12.0 vs. 16.0%, p = 0.39). The former compared to the latter group had similar odds for SAB (OR 1.56, 95%CI: 0.68-3.58, p = 0.293), MP (OR 1.40, 95%CI: 0.47-4.15, p = 0.544), and non-CP (OR 0.66, 95%CI: 0.28-1.58, p = 0.355). Likewise, when analyzed as a continuous variable, follicular phase length did not significantly impact the odds for SAB (OR 1.07, 95%CI: 0.99-1.14, p = 0.07), MP (OR 1.01, 95%CI: 0.94-1.10, p = 0.743), or non-CP (OR 0.98, 95%CI: 0.90-1.07, p = 0.687). Endometrial thickness was increased in cycles with a longer compared to shorter follicular phase with an adjusted mean difference of 1.12 mm (95% CI: 0.93-1.31, p < 0.001). Furthermore, endometrial thickness increased by 0.12 mm (95% CI: 0.09-0.15, p <0.001) with each additional follicular phase day. In gonadotropin-induced IUI cycles, a longer follicular phase is associated with increased endometrial thickness and possibility of clinical pregnancy.

Discordant ovarian reserve testing is a predictor of lower clinical pregnancy during COH-IUI fertility treatment

Patients with poor ovarian reserve often have a diminished response to controlled ovarian hyperstimulation (COH). Both Anti-Mullerian hormone (AMH) and Day-3 FSH levels have been shown to independently reflect ovarian reserve and are predictive of pregnancy success rates. However, when the levels are discordant, it is unclear how to counsel patients. At present no studies have evaluated COH-IUI outcomes in women with discordant FSH and AMH levels. This study was designed to evaluate pregnancy outcomes in women with discordant FSH and AMH levels after COH fertility treatment. Retrospective Cohort of 745 women. Excluding only women with polycystic ovarian syndrome, data from all fertility patients undergoing COH cycles during the period June, 2013 through March 2017 were studied. Women were considered to have normal Day-3 FSH with value <10 (mIU/mL), and normal AMH if values fell within age specific reference value. Clinical pregnancy rate is the cumulative pregnancy achieved after maximum of three cycles of COH with or without IUI. Chi- Square were used for statistical analysis using SPSS. Table below show as expected, concordant abnormal AMH/FSH values (Grp D) have significantly lower pregnancy rate than concordant normal (Grp A) patients. Abnormal FSH discordance (Grp C) have an intermediate pregnancy rate, statistically lower than normal concordance but significantly higher than abnormal concordant group. Patients with discordant abnormal AMH/normal FSH (Grp B) were not statistically different from abnormal concordance group but significantly lower than normal concordant group. There was no statistical difference in mean age or BMI among the four groups.Tabled 1GroupsABCD%Pregnant (n/N)64.2%(300/467)7.9%(9/114)32.2%(30/93)14.1%(10/71)Statistical comparisons: A vs. D p<0.0001; A vs B p<0.0001; A vs. C p<0.001; C vs. D p<0.04; B vs. D p>0.05(NS). Open table in a new tab Statistical comparisons: A vs. D p<0.0001; A vs B p<0.0001; A vs. C p<0.001; C vs. D p<0.04; B vs. D p>0.05(NS). To the best of our knowledge, this is the first study to investigate pregnancy outcomes in women with discordant Day-3 FSH and AMH levels after non-IVF COH fertility treatment. The data clearly indicate that women with discordant FSH and AMH levels will frequently have lower clinical pregnancy rates after fertility treatment.This investigation also showed that, irrespective of age, low AMH, whether combined with a normal or high FSH level, is predictive of poor fertility treatment outcome. Abnormal Day-3 FSH in the presence of a normal AMH is also a predictor of decreased pregnancy success but the prognosis is not as poor as when the AMH is abnormal. Our data support obtaining a Day-3 FSH value in patient with normal AMH to be able to more accurately counsel them about their prognosis for pregnancy success.

Modified natural cycle for embryo transfer using frozen-thawed blastocysts: A satisfactory option

ObjectiveTo describe pregnancy outcomes of frozen-thawed blastocysts cycles using modified natural cycle frozen embryo transfers (NC-FET) and down-regulated hormonally controlled frozen embryo transfers (HC-FET) protocols. Study designThis retrospective cohort study included all patients undergoing either modified NC-FET or down-regulated HC-FET using frozen-thawed day 5 embryos. Cycles with donor blastocysts were excluded. Four hundred twenty eight patients underwent a total of 493 FET cycles. Patients with regular menses and evidence of ovulation underwent modified NC-FET. These patients were given hCG 10,000 IU IM on the day of LH-surge. Vaginal progesterone (P4) was started two days later and blastocyst transfer was planned seven days after detecting the LH surge. Anovulatory patients and some ovulatory patients underwent down-regulated HC-FET. These patients were placed on medroxy-progesterone acetate (10mg) for 10days to bring on menses and were also given a half-dose of GnRH-agonist (GnRH-a) on the third day of medroxy-progesterone acetate. Exogenous estradiol was initiated on the third day of menses. Once serum E2 levels reached >500pg/mL and endometrial lining reached >8mm, intramuscular (IM) P4 in oil was administered. Blastocyst FET was planned 6days after initiating P4. The primary outcomes included clinical pregnancy and delivery rates. ResultsThere were 197 patients in the modified NC-FET protocol and 181 in the down-regulated HC-FET protocol. Mean age (years), day-3 FSH levels (mIU/mL) and percentage of patients with male factor infertility were significantly higher and mean BMI (kg/m2) was significantly lower in modified NC-FET compared to HC-FET, respectively. Analysis of the first cycle pregnancy outcomes revealed no significant differences in clinical pregnancy rate (54.3% vs. 52.5%) and delivery rate (47.2% vs. 43.6%) between modified NC-FET and HC-FET. Logistic regression analysis showed age (OR=0.939, 95% CI 0.894–0.989, p=0.011), number of blastocysts transferred (OR=1.414, 95% CI 1.046-1.909, p=0.024), and the year of FET (OR=1.127, 95% CI 1.029-1.234, p=0.010) were significant factors impacting clinical pregnancy. An age analysis within three age groups (≤35, 36–39, ≥40) was performed, but no significant difference in clinical pregnancy was observed. ConclusionOur data suggests that modified NC-FET protocol has comparable pregnancy outcomes to down-regulated HC-FET when utilizing frozen-thawed day 5 embryos.

The impact of total gonadotropin dose on spontaneous abortion rates and early pregnancy outcomes in infertile couples undergoing gonadotropin induction/intrauterine insemination cycles

Studies suggest that ovarian hyperstimulation with high dose gonadotropin regimens in women undergoing IVF may affect endometrial receptivity, as well as oocyte and embryo quality [1, 2]. Furthermore, high doses of gonadotropins increase aneuploidy rates in animal models and are suspected to increase aneuploidy in human embryos [3]. The potential impact of high dose gonadotropins on spontaneous abortion rates (SABR) and early pregnancy outcomes in gonadotropin induced/intrauterine insemination (Gn/IUI) cycles is unknown. To evaluate the impact, if any, of total gonadotropin dose on SABR (surrogate outcome for aneuploidy), and early pregnancy outcomes in Gn/IUI cycles. Design: Retrospective cohort. Setting: Academic fertility center Interventions: A total of 2099 Gn/IUI cycles (12/2003-1/2016; 923 patients) were analyzed. Exclusion criteria included: i) age older than (≥) 38 years, ii) body mass index (BMI) above (≥) 35 kg/m2, iii) diagnosis of diminished ovarian reserve or polycystic ovary syndrome. Cycles were stratified by total gonadotropin dose i) into two groups: ≤ and > 75th percentile (Gr1 and Gr2, respectively), and ii) into quartiles (Q1-Q4). Outcome Measures: Primary outcome measure was the rate of SAB per cycle. Secondary outcome measures included: clinical, multiple, and non-clinical (ectopic/biochemical) pregnancy rates (CPR, MPR, and non-CPR, respectively). Statistics: t-test, Mann Whitney U- and χ2- tests were used as appropriate for comparisons between groups 1 and 2. Using logistic regression models, odds ratios (ORs) and 95% confidence intervals (CI) were calculated for SAB, clinical, and non-clinical pregnancy across quartiles adjusting for potential confounders (age, BMI, day-3 FSH, infertility diagnosis and endometrial thickness). P<0.05 was considered statistically significant. Table 1 summarizes the demographics and cycle characteristics of the study population stratified by the 75th percentile cut-off. Patients receiving total gonadotropin dose >75th percentile, when compared to those receiving doses ≤75th percentile, experienced similar SABR (18.6 vs. 12.9%, p = 0.19; for Gr2 vs. Gr1, respectively). However, CPR was significantly higher in the former (>75th) compared to the latter (≤75th) group (19.1 vs. 13.2% for Gr2 vs. Gr 1, respectively, p <0.05), while MPR and non-CPR were comparable between the two groups (13.5 vs. 12.9%, p = 0.88; and 7.7 vs. 6.6%, p = 0.72 for Gr2 vs. Gr 1, respectively). Similarly, when calculating adjusted OR (95%CI) across quartiles of total Gn dose, using Q1 as the reference group, we noted no differences in the incidence of SAB and non-clinical pregnancy (Fig. 1A-B), while the OR for clinical pregnancy was significantly higher in both Q3 and Q4 and nearly significant in Q2 compared to Q1 (Fig. 1C). Despite evidence of potential adverse effects of higher Gn doses on oocyte and embryo quality and possibly on endometrial receptivity in IVF cycles, the overall lower doses of stimulation medication administered during Gn/IUI cycles, do not seem to have a similar negative impact on SABR and early pregnancy outcomes.

Bisphenol A and Ovarian Reserve among Infertile Women with Polycystic Ovarian Syndrome.

To better understand possible effects of bisphenol A (BPA) exposure on ovarian reserve in women with polycystic ovary syndrome (PCOS), we measured creatinine adjusted urinary BPA (BPA_Cre) concentrations and used regression models to evaluate the association between urinary BPA level and antral follicle count (AFC), antimullerian hormone (AMH), day-3 follicle stimulating hormone levels (FSH) and inhibin B (INHB) in 268 infertile women diagnosed with PCOS. BPA was detected in all women with a median concentration of 2.35 ng/mL (the 25th and 75th percentiles of 1.47 ng/mL and 3.95 ng/mL). A unit increase in BPA_Cre was associated with a significant decrease of 0.34 in AFC (β = −0.34, 95% CI = −0.60, −0.08; p = 0.01). Likewise, BPA was negatively associated with AMH and day-3 FSH levels, but neither of them reached statistical significance. No association was observed between BPA and INHB. Our results suggest that in women with PCOS, BPA may affect ovarian follicles and, therefore, reduce ovarian reserve.

Should Ovulation Induction/Intrauterine Insemination Be Offered to Women With Tubal Factor Infertility? [24G

INTRODUCTION: The purpose of this study is to evaluate the outcomes of ovulation induction/intrauterine insemination (OI/IUI) in patients with tubal factor infertility (TFI) and at least one patent fallopian tube compared to patients with idiopathic infertility (II). METHODS: Design: Retrospective. Setting: Academic fertility center. Patients/Interventions: Data from 630 OI/IUI cycles were analyzed. Cycle outcomes of patients with TFI (125 cycles) were compared to those of an age-matched control group (1:3) of women with II (505 cycles). Outcome measures: Clinical pregnancy (CPR), ectopic pregnancy (ectPR), spontaneous abortion (SABR) rates per cycle, and cumulative clinical pregnancy rates (cumCPR). Statistics: t tests and chi-square, as appropriate. RESULTS: The groups did not differ in age, BMI, day-3 FSH, peak E2, day of hCG trigger, or total motile sperm count (mean±SD 34.2±3.8 vs 34.4±3.8 years, P=.81; 24.1±4.1 vs 24.1±4.4 kg/m2, P=1.00; 7.1±2.0 vs 6.8±2.2IU, P=.44; 464.2±222.8 vs 562.8±287.5 pg/mL, P=.25; 11.3±2.3 vs 10.9±2.2, P=.07; 66.1±59.5 vs 60.6±71.2 million, P=.48; for TFI vs II, respectively). However, TFI patients required a higher total gonadotropin dose compared to women with II (720.5±531.2 vs 579.388.2±388.2 IU, P=.005, respectively). CPR, cumCPR, and SABR were comparable between groups (8.9% vs 11.4%, P=.52; 25.9% vs 34.7%, P=.25; 21.4% vs 18.8%, P=1.00, for TFI vs II, respectively). A higher ectPR was noted among TFI patients (2/14 vs 1/64, P=.08, respectively), though the difference did not reach statistical significance. CONCLUSION: OI/IUI should be considered in patients with TFI with at least one patent fallopian tube, since cycle outcomes do not differ significantly from those of women with II undergoing the same type of treatment.

Serum tumor necrosis factor-α, interleukin-6, monocyte chemotactic protein-1 and paraoxonase-1 profiles in women with endometriosis, PCOS, or unexplained infertility.

To investigate the serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and Paraoxonase-1 (PON-1) during fertility treatment of women with endometriosis (Endo), PCOS or unexplained infertility (Unexpl). Thirty-six patients with Endo, PCOS or Unexpl undergoing controlled ovarian stimulation for IVF or IUI were consented and their serum, on day-3 (baseline) and at the end of FSH treatment (peak), was collected and investigated for levels of TNF-α, IL-6, MCP-1, and PON-1. Correlations, ANOVA and Student's t-test were used for statistical analysis. Peak serum levels of IL-6, MCP-1 and PON-1 were positively correlated to E2 peak levels. TNF-α levels were inversely correlated to estradiol levels and they were lower in patients who ultimately became pregnant when compared to non-pregnant (P < 0.05). Mean TNF-α levels were significantly higher in Unexpl group (P < 0.05). The mean levels of IL-6, and MCP-1 were significantly (p < 0.05) higher in women with PCOS compared with Endo and Unexpl. No differences were found between the three clinical groups in patient's age, BMI, Day-3 FSH, PON-1 and pregnancy outcome. Circulating cytokine levels were influenced by ovarian stimulation, as demonstrated by increased levels of IL-6, MCP-1 and PON-1, and decreased level of TNF-α at the end of controlled ovarian stimulation. While evidence of relationship between circulating cytokines with mild endometriosis was not found, PCOS was associated with elevated serum IL-6 and MCP-1 but lower TNF-α concentration. Unexplained infertility was associated with elevated TNF-α level. No relationship between serum PON-1 concentration and PCOS, mild endometriosis or unexplained infertility was noted.

Normal-range FMR1 repeat genotypes and correlation with serum anti-müllerian hormone (AMH), cycle day 3 FSH (D3FSH), antral follicle count (AFC) and incidence of diminished ovarian reserve (DOR)

FMR1 mutation and premutation carriers are known to be at risk for premature-ovarian failure. Conflicting studies have investigated correlations between particular normal FMR1 genotypes and AMH levels or incidence of DOR. This large study assessed potential associations across all FMR1 genotypes with respect to AMH, D3FSH, AFC and incidence of DOR.

Ovarian reserve and PGD treatment outcome in women with myotonic dystrophy

Myotonic dystrophy (DM) is the most common form of muscular dystrophy in adults. There are conflicting reports about its effect on female fertility. This study investigated ovarian reserve and IVF–preimplantation genetic diagnosis (PGD) outcome in women with DM1. A total of 21 women undergoing PGD for DM1 were compared with 21 age- and body mass index-matched women undergoing PGD for other diseases. Ovarian reserve markers, response to stimulation, embryo quality and clinical pregnancy and live birth rates were compared. Day-3 FSH concentration was higher, while anti-Müllerian hormone concentration and antral follicle count were lower in the DM1 group (median, range: 6.9 (1.8–11.3) versus 5.7 (1.5–10.7)IU/l; 0.9 (0.17–5.96) versus 2.68 (0.5–9.1)ng/ml; and 13 (0–63) versus 23 (8–40) follicles, respectively, all P<0.05). Total FSH dose was higher (5200 versus 2250IU, P=0.004), while the numbers of oocytes retrieved (10 versus 16, P<0.04) and metaphase-II oocytes (9 versus 12, P<0.03) were lower in the DM1 group. The number of cycles with top-quality embryos and the clinical pregnancy rate were lower in the DM1 group. In conclusion, there is evidence of diminished ovarian reserve and less favourable IVF–PGD outcome in women with DM1.Myotonic Dystrophy (DM) is the most common form of muscular dystrophy in adults. There is evidence of subfertility in males affected with the disease but conflicting reports about the effect of the disease on female fertility. The aim of our study was to investigate ovarian reserve and IVF–PGD results in women with DM. Twenty-one women undergoing preimplantation genetic diagnosis (PGD) treatment for DM were compared to 21 age- and BMI matched women undergoing PGD treatment for other diseases. The two groups were compared for antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) levels (the best known markers of ovarian reserve and fertility potential), ovarian response, embryo quality and pregnancy and live birth rates. AFC and the AMH levels were statistically significant lower in the DM group. Total medication dose needed for ovarian stimulation was higher, the number of oocytes and mature oocytes retrieved, and the number of cycles with top quality embryos were lower in the DM group compared to the controls. In conclusion, there is evidence of diminished ovarian reserve, and less favorable IVF-PGD outcome in women with DM. Therefore, we recommend advising these women about the possibility of early decreasing ovarian function in order to prevent any delay in reproductive planning.

The association of bisphenol-A urinary concentrations with antral follicle counts and other measures of ovarian reserve in women undergoing infertility treatments

In this prospective cohort of women undergoing infertility treatments, we measured specific-gravity adjusted urinary BPA (SG-BPA) concentrations and used regression models to evaluate the association of BPA with antral follicle count (AFC), day-3 serum follicle stimulating hormone levels (FSH), and ovarian volume (OV). BPA, detected in >80% of women, had a geometric mean (±GSD) of 1.6±2.0, 1.7±2.1, and 1.5±1.8μg/L for the women contributing to the AFC (n=154), day-3 FSH (n=120), and OV (n=114) analyses, respectively. There was an average decrease in AFC of 12% (95% CI: −23%, −0.6%), 22% (95% CI: −31%, −11%), and 17% (95% CI: −27%, −6%), in the 2nd, 3rd, and 4th SG-BPA quartile compared to the 1st quartile, respectively (p-trend: <0.001). No association of SG-BPA with FSH or OV was observed. Among women from an infertility clinic, higher urinary BPA concentrations were associated with lower AFC, raising concern for possible accelerated follicle loss and reproductive aging.

A novel therapy with sitagliptin for metformin-ineffective aged art repeaters: increase in pregnancy rate by decreasing postprandial glycemic levels and advanced glycation endproducts

A novel therapy with sitagliptin for metformin-ineffective aged art repeaters: increase in pregnancy rate by decreasing postprandial glycemic levels and advanced glycation endproducts

Use of zebrafish larvae's swimming behavior to study brain development

In this prospective cohort of women undergoing infertility treatments, we measured specific-gravity adjusted urinary BPA (SG-BPA) concentrations and used regression models to evaluate the association of BPA with antral follicle count (AFC), day-3 serum follicle stimulating hormone levels (FSH), and ovarian volume (OV). BPA, detected in >80% of women, had a geometric mean (±GSD) of 1.6 ± 2.0, 1.7 ± 2.1, and 1.5 ± 1.8 μg/L for the women contributing to the AFC (n = 154), day-3 FSH (n = 120), and OV (n = 114) analyses, respectively. There was an average decrease in AFC of 12% (95% CI: −23%, −0.6%), 22% (95% CI: −31%, −11%), and 17% (95% CI: −27%, −6%), in the 2nd, 3rd, and 4th SG-BPA quartile compared to the 1st quartile, respectively (p-trend: <0.001). No association of SG-BPA with FSH or OV was observed. Among women from an infertility clinic, higher urinary BPA concentrations were associated with lower AFC, raising concern for possible accelerated follicle loss and reproductive aging.

S5-2: Science for or science based regulation: Is there a missing link?

In this prospective cohort of women undergoing infertility treatments, we measured specific-gravity adjusted urinary BPA (SG-BPA) concentrations and used regression models to evaluate the association of BPA with antral follicle count (AFC), day-3 serum follicle stimulating hormone levels (FSH), and ovarian volume (OV). BPA, detected in >80% of women, had a geometric mean (±GSD) of 1.6 ± 2.0, 1.7 ± 2.1, and 1.5 ± 1.8 μg/L for the women contributing to the AFC (n = 154), day-3 FSH (n = 120), and OV (n = 114) analyses, respectively. There was an average decrease in AFC of 12% (95% CI: −23%, −0.6%), 22% (95% CI: −31%, −11%), and 17% (95% CI: −27%, −6%), in the 2nd, 3rd, and 4th SG-BPA quartile compared to the 1st quartile, respectively (p-trend: <0.001). No association of SG-BPA with FSH or OV was observed. Among women from an infertility clinic, higher urinary BPA concentrations were associated with lower AFC, raising concern for possible accelerated follicle loss and reproductive aging.