Clomiphene Citrate Cycles Research Articles

The impact of clomiphene citrate on the endometrium in comparison to gonadotropins in intrauterine insemination cycles: is it thinner and does it matter?

To determine whether endometrial thickness (EMT) differs between i) clomiphene citrate (CC) and gonadotropin (Gn) utilizing patients as their own controls, and ii) patients who conceived with CC and those who did not. Furthermore, to investigate the association between late-follicular EMT and pregnancy outcomes, in CC and Gn cycles. Retrospective study. Three sets of analyses were conducted separately for the purpose of this study. In analysis 1, we included all cycles from women who initially underwent CC/IUI (CC1, n=1252), followed by Gn/IUI (Gn1, n=1307), to compare EMT differences between CC/IUI and Gn/IUI, utilizing women as their own controls. In analysis 2, we included all CC/IUI cycles (CC2, n=686) from women who eventually conceived with CC during the same study period, to evaluate EMT differences between patients who conceived with CC (CC2) and those who did not (CC1). In analysis 3, pregnancy outcomes among different EMT quartiles were evaluated in CC/IUI and Gn/IUI cycles, separately, to investigate the potential association between EMT and pregnancy outcomes. In analysis 1, when CC1 was compared to Gn1 cycles, EMT was noted to be significantly thinner [Median (IQR): 6.8 (5.5-8.0) vs. 8.3 (7.0-10.0) mm, p<0.001]. Within-patient, CC1 compared to Gn1 EMT was on average 1.7mm thinner. Generalized linear mixed models, adjusted for confounders, revealed similar results (coefficient: 1.69, 95% CI: 1.52-1.85, CC1 as ref.). In analysis 2, CC1 was compared to CC2 EMT, the former being thinner both before [Median (IQR): 6.8 (5.5-8.0) vs. 7.2 (6.0-8.9) mm, p<0.001] and after adjustment (coefficient: 0.59, 95%CI: 0.34-0.85, CC1 as ref.). In analysis 3, clinical pregnancy rates (CPRs) and ongoing pregnancy rates (OPRs) improved as EMT quartiles increased (Q1 to Q4) among CC cycles (p<0.001, p<0.001, respectively), while no such trend was observed among Gn cycles (p=0.94, p=0.68, respectively). Generalized estimating equations models, adjusted for confounders, suggested that EMT was positively associated with CPR and OPR in CC cycles, but not in Gn cycles. Within-patient, CC generally resulted in thinner EMT compared to Gn. Thinner endometrium was associated with decreased OPR in CC cycles, while no such association was detected in Gn cycles.

Recent clomiphene citrate exposure does not impact subsequent clinical outcomes in single euploid frozen embryo transfer cycles

Do infertile couples who recently utilized clomiphene citrate (CC) for ovulation induction or ovarian stimulation (<90 days previously) followed by a single euploid embryo transfer (SEET) have lower implantation potential compared with patients who were not exposed to CC within 90 days before embryo transfer (ET)? There does not appear to be an association between recent CC exposure and lower implantation potential in patients who undergo a frozen embryo transfer (FET) of euploid embryos. Clomiphene has been found to be associated with lower pregnancy rates when compared against other ovarian stimulation medications. The majority of published research about the effects of CC on implantation potential suggest an anti-estrogenic effect on the endometrium. Quality evidence and information about utilization of CC and its effect on implantation potential after euploid ETs is lacking in the literature. A retrospective cohort study with propensity score matching was carried out. We included all patients that underwent an autologous SEET from September 2016 to September 2022 at a single academic-private ART center. The study group included patients that had utilized CC during either ovulation induction cycles and/or controlled ovarian stimulation at least 90 days before FET. A propensity score-matched control group of patients that were unexposed to CC within 90 days prior to SEET was used for comparisons. The primary outcome was positive pregnancy test (defined as a positive serum β-hCG measured 9 days after ET), with other outcomes including clinical pregnancy, ongoing pregnancy, biochemical pregnancy loss, and clinical pregnancy loss rates per SEET. Multivariate regression analyses fitted with generalized estimating equations were utilized to analyze if there was an association between CC utilization and IVF outcomes. Furthermore, the study evaluated the cumulative effect of CC and endometrial receptivity in vivo and subsequent IVF outcomes. A total of 593 patients with utilization of CC in <90 days before ET were compared with 1779 matched controls. Positive pregnancy test rates were comparable among the control group and the CC exposed groups, respectively (74.3% versus 75.7%, P = 0.79), as were clinical pregnancy (64.0% versus 65.0%, P = 0.60), ongoing pregnancy (51.8% versus 53.2%, P = 0.74), biochemical pregnancy loss (15.7% versus 14.03%, P = 0.45), and clinical pregnancy loss rates were also comparable among cohorts (17.1% versus 18.1%, P = 0.71). No association was found between utilization of clomiphene and lower implantation rates (adjusted odds ratio 0.95, 95% CI 0.76-1.18). Also, no differences were observed in sub-analyses based on multiple CC utilization periods. Finally, no association was found between the number of consecutive cumulative clomiphene cycles and sub-optimal IVF outcomes. The study has inherent bias that originated from its retrospective design. Serum levels of CC were not measured and sample size for the sub-analyses was small. There does not appear to be an association between recent CC exposure and lower implantation potential in patients who undergo a FET of euploid embryos. This finding remains consistent, even in patients who undergo multiple, consecutive clomiphene cycles prior to ET. There were no long-term effects of CC on endometrial development and clinical characteristics examined in this study. Patients that utilized CC medication prior to a SEET cycle for either ovarian stimulation or ovulation induction, can be assured that there is no evidence of a residual effect of recent CC administration that could jeopardize their pregnancy probability. No funding was received for the realization of this study. A.C. is advisor and/or board member of Sema4 (stakeholder in data) and Progyny. The other authors have no conflicts of interest to declare. N/A.

Hormonal changes in consecutive clomiphene citrate stimulation cycles and their effect on pregnancy rates.

Objective:To determine the relationship between the cumulative effect of sequential clomiphene citrate (CC) treatments in unexplained infertile women with intercycle and intracycle serum hormone changes.Materials and Methods:Patients who received CC 50 mg in the first cycle (group I, n=34) as ovulation induction and those who received CC 50 mg in the second consecutive cycle (group II, n=18) were compared. Basal (cycle days 2-5) and trigger day (the day that recombinant human chorionic gonadotropin is given) levels of gonadotropin and steroid hormones were measured.Results:The 17OHP increase on trigger day was found to be statistically significantly higher in group II compared to the basal day (p=0.083). The testosterone (T) response on the trigger day of the patients in group II was found to be statistically significantly higher than that in group I (p=0.023). The number of selected follicles was negatively correlated with a follicle-stimulating hormone decrease and positively correlated with an estradiol increase. Endometrial thickness was positively correlated with a luteinizing hormone increase, and cycle cancelation was positively correlated with decreased estradiol.Conclusion:Based on this study, it was concluded that the reason for the increased efficiency rate in successive cycles of CC may be the cumulative increase in T and 17OHP levels. However, this result was found not to affect the clinical pregnancy rate.

P-342 The impact of Clomiphene Citrate (CC) on the endometrium in comparison to gonadotropins (Gn) in intrauterine-insemination treatments (IUI): Is it thinner and does it matter?

Abstract Study question Utilizing patients as their own controls, does endometrial thickness (EMT) differ between CC/IUI and Gn/IUI? Does EMT differ between CC-cycles with and without associated conception? Summary answer Within-patient, CC resulted in thinner EMT compared to Gn. CC-cycles associated with conception compared to the ones without it, had thicker endometria. What is known already CC, unlike gonadotropins, may have an anti-estrogenic effect on the endometrium. Concerns exist that the thinning of the endometrium might be associated with altered endometrial development and receptivity. However, available data in CC cycles remain inconsistent, probably due to patient and protocol heterogeneity. Currently, it remains unclear whether CC treatments produce a thinner endometrium, compared to gonadotropins, in the same patient. Furthermore, it is uncertain whether such a difference, if one exists, has a consequential effect on IUI cycle outcomes. Study design, size, duration Design: retrospective. Duration: 1/2004-9/2021 Cohort 1 utilized women as their own controls to evaluate CC’s impact on the endometrium and included all cycles from women who sought fertility treatments and initially underwent CC/IUI (CC1, n = 1252) followed by Gn/IUI (Gn1, n = 1307). Cohort 2 included all cycles from women seeking fertility treatments at the same center that conceived following CC/IUI treatments (CC2, n = 686). EMT was compared between groups (CC1 vs. Gn1, CC1 vs. CC2). Participants/materials, setting, methods Outcome measures: Primary: EMT (mm). Secondary: HCG-positivity (pos-HCGR), clinical pregnancy (CPR), and spontaneous abortion rates (SABR). Statistics: Regression analysis was used to calculate Odds Ratios (OR) with associated 95% confidence intervals (95%CI), adjusting for potential confounders [maternal age, Body Mass Index (BMI), prior parity, day of EMT measurement relative to trigger). Generalized estimating equations (GEE) model were utilized to account for multiple cycles per patient. P &amp;lt; 0.05 was considered significant. Main results and the role of chance In cohort 1, despite CC1 exhibiting non-inferior ovarian response compared to Gn1 (as assessed by preovulatory follicular number), EMT was significantly thinner in CC1 compared to Gn1 [Median(IQR): 7.0(5.7-8.3) vs. 8.9(7.4-10.0), p&amp;lt;.001]. When CC1 was compared to CC2 (CC conceiving), EMT was also thinner [Median(IQR): 7.0(5.7-8.3) vs. 7.5(6.2-9.0), for CC1 vs. CC2, respectively, p&amp;lt;.001]. A higher percentage of CC1 compared to Gn1 cycles resulted in EMT≤7mm (48.9% vs. 16.7% , for CC1 vs. Gn, respectively; p&amp;lt;.001). Most subsequent Gn cycles (82.8%), in the same women, resulted in thicker EMT compared to CC1. AdjOR, in generalized linear mixed models, suggested that CC2 when compared to CC1 cycles had thicker EMT [adjOR(95%CI): 1.81, (1.41,2.35), p&amp;lt;.001]. Interestingly, clinical pregnancies were observed even when EMT was ≤4mm in both CC2 and Gn1 groups and SABR did not differ between cycles with EMT≤4mm and the ones with thicker EMT (2.5% vs. 11.5%, p=.258, in CC2; 0% and 12.3%, p=.544, in Gn1; SABR EMT ≤4 vs. 4 mm, respectively). GEE models suggested an association between EMT and CPR in CC cycles (CC1&amp;CC2), [adjOR(95%CI): 1.12(1.07,1.18), p&amp;lt;.001)] while in Gn1, no such association was observed. Limitations, reasons for caution Our study was limited by its retrospective design. Reflecting our selection criterion, in cohort 1, most CC cycles did not result in pregnancy, restricting relevant comparisons. Number of cycles resulting in EMT ≤7mm, and particularly ≤4mm, was limited, and consequently respective results should be interpreted cautiously. Wider implications of the findings Utilizing patients as their own controls, we showed that CC compared to gonadotropins resulted in thinner endometrium. Given comparable follicular response, and potentially estradiol levels, thinner endometrium might have resulted from CC’s anti-estrogenic effect. Furthermore, patients conceiving on CC had a thicker endometrium compared to the ones that did not. Trial registration number NA

P-102 Progesterone luteal-phase support during IUI cycle should be added depending on women age and/or on previous mid-luteal progesterone assessment to promote live births

Abstract Study question To determine the Mid-luteal progesterone (MLP) threshold which could condition live-birth (LB) after IUI, and effects of additional progesterone luteal-phase support (LPS) in subsequent cycles. Summary answer MLP threshold is age-dependant. LPS should only be used if previous MLP is below the age related threshold, as its inappropriate use reduces LB rate. What is known already Progesterone is essential to prepare and maintain the uterus suitable for a possible pregnancy. During IUI, it is not clear if LPS is beneficial to obtain a live birth, and whether it should be introduced systematically or only in women with a low MLP assessment during a previous cycle. Study design, size, duration In an audit purpose, we performed a retrospective uni-centric analysis of 705 IUl cycles performed from January 2015 to March 2020 in couples which fertility work-up concluded to unexplained infertility, mild male infertility or PCOS with no pregnancy after 3 cycles of clomiphene citrate. Our primary outcome was LB. Participants/materials, setting, methods IUI was performed after ovarian stimulation with gonadotrophins. MLP was assessed using immuno assay method, days 7 post-IUI. LPS (Cyclogest® 200 mg/day) was added when consultant considered former cycle’s MLP was too low. MLP thresholds were defined without LPS using a ROC Curve, considering subgroups of patient’s age. LB rate was analyzed using Multivariate Gill Andersen models to take into account repetitions of IUI cycles. Prognostic factors for LBR were investigated using a Cox model. Main results and the role of chance Women were 33.6±3.9 years old. We obtained 99 (14%) LB. In women who didn’t receive LPS, regardless of their age, MLP threshold was 57.5 nmo/l (AUC=0.57). Multivariate logistic regression modeling identified MLP assessment as a significant prognostic factor for obtaining LB after IUI (OR = 1.668, CI95%[1.023; 2.721], p = 0.0402). When also considering women’s age, a cut-off of 36 years old was computed which allowed more fitted age-related MLP thresholds for obtaining LB after IUI. In women &amp;lt;36 years old, MLP threshold was 39.5 nmol/l (AUC=0.57) whereas it was 60.5 nmol/L (AUC=0.57) for age ≥36. Age-related thresholds were more predictive of LB than initial age independent threshold according to Akaike Criteria (1168.48 versus 1198.96, respectively). Using the whole population (i.e. receiving or not LPS), the multivariate analysis highlighted that, compared to women with MLP above their age related threshold who (appropriately) didn’t receive LPS: - Women below their age-related MLP threshold who appropriately receive LPS had similar LB rate: OR = 0.5474, CI95%[0.1857-1.6138], p = 0.2747. - Women below their age-related MLP threshold who didn’t receive LPS (inappropriately) had a significantly lower LB rate: OR = 0.4794, CI95%[0.2727-0.8427], p = 0.0106. - Women above their age-related MLP threshold who received LPS (inappropriately) had a significantly lower LB rate: OR = 0.5627, CI95%[0.3302-09587], p = 0.0433. Limitations, reasons for caution Because of the retrospective design of our study and because of the limited number of included couples, our results should be considered with caution. Confirmation is needed with further prospective studies with a larger number of participants. Wider implications of the findings Our study highlight for the first time the impact of age on the LPS strategy after IUI, and emphases the need for personalized fertility medicine based on previous MLP assessment when considering LPS. Trial registration number No needed, NHS Audit

Hormonal Changes in Clomiphene Citrate Cycles in Unexplained Infertility Can Predict Follicle Development?

To examine the intra-cycle and inter-cycle hormonal changes in the clomiphene citrate (CC) cycle in women with unexplained infertility; and to determine the factors that may predict follicle development or CC failure. Descriptive study. This study was conducted at the Bagcilar Training and Research Hospital, Istanbul, Turkey from August 2019 to March 2020. Fifty-two women with unexplained infertility were included. Fifty-two cycles given 50 mg of CC but without follicle development were accepted as Group I. In the next cycle, 48 cycles given 100 mg of CC were accepted as Group II. During every cycle, serum hormone (FSH, LH, E2, P4, A4, DHEA‑S, T, 17‑OHP) levels were measured on days 2, 3, 4 or 5 of the cycle (basal day), and on the days when the leading follicle was triggered (trigger day). Endogenous hormone changes were compared in both the groups with and without follicle development as well as in those who could conceive and those who could not conceive. Basal day FSH and DHEA‑S values were found to be statistically significantly higher in women with follicle development than those without follicle development (p = 0.02 and p = 0.039, respectively). The trigger day FSH value was found to be significantly lower in women who conceived compared to the basal day value (p = 0.004). The relatively high P4 value (p = 0.008) on the basal day (contingent upon it was not exceeding the 0.5 ng/mL threshold) and the low FSH value (p = 0.015) on the trigger day were found to be statistically significantly different in women who had conceived compared to those who had not. Basal serum FSH, P4 and DHEA‑S levels can be used as predictors of ovulation in CC cycles in women with unexplained infertility by determining a threshold value with more comprehensive studies to be conducted in the future. Key Words: Androgens, Ovarian stimulation, Clomiphene citrate, Unexplained infertility, Induction of ovulation, Prediction.

Use of uterine artery Doppler velocimetry values to predict pregnancy in intrauterine insemination cycles in couples with unexplained infertility

Background/Aim: It is known that pregnancy success in IUI cycles performed in couples with unexplained infertility is below 20% even under the best conditions. Predicting the success in IUI cycles and directing patients to appropriate assisted reproductive treatment is essential for the time and budget. In this context, we aimed to investigate the use of uterine artery Doppler velocimetry values to predict pregnancy in intrauterine insemination (IUI) cycles in couples with unexplained infertility. Methods: In this prospective cohort study, couples with unexplained infertility were randomly assigned to two groups: clomiphene citrate (CC) and gonadotropin. The CC group used 50-150 mg CC daily between the 5th and 9th days of the menstrual period, while the gonadotropin group used 37.5-75 IU of recFSH daily from the 3rd day of the menstrual period until the dominant follicle developed. Ovulation was triggered by recHcg when at least one dominant follicle of 17 mm or larger was detected. Intrauterine insemination was performed 36 hours after the trigger. Uterine artery flow pulsatility index (PI), resistance index (RI)and the systolic-diastolic ratio (S/D) were measured in all patients by Doppler ultrasound on the 3rd day of menstruation and trigger day. Uterine artery Doppler values of the group that achieved pregnancy and those who could not conceive were compared as the main outcome of the study. Results: The study was designed over 143 IUI cycles, 89 cycles in the gonadotropin group and 54 cycles in the CC group. In 143 IUI cycles, 24 (16%) pregnancies were obtained, seven (12%) in the CC group and 17 (12%) in the gonadotropin group. In both CC and gonadotropin cycles, mean age, BMI, duration of infertility, hormone levels on the third day of menstruation, endometrial thickness on 3rd day of menstruation and on the trigger day, dominant follicle number and mean follicle diameter were similar in the pregnant and non-pregnant groups (P<0.05). There was no statistical difference in uterine artery Doppler values (RI, PI and S/D) measured neither on the 3rd day of the cycle nor on the trigger day between pregnant and non-pregnant groups in patients receiving CC or gonadotropin (P<0.05). Conclusion: Considering the hormonal changes in stimulated cycles or other factors that may have an impact on endometrial blood flow and endometrial receptivity, we think that only uterine artery Doppler velocity measurement values are not effective in predicting pregnancy success in CC or gonadotropin-induced IUI cycles.

THE ASSOCIATION BETWEEN OVULATORY SURGE TYPE AND PREGNANCY OUTCOME AMONG PATIENTS UNDERGOING INTRAUTERINE INSEMINATION

To determine whether ovulatory surge type (human chorionic gonadotropin (hCG) ovulatory trigger, endogenous luteinizing hormone (LH) surge, or a combination of both) is associated with pregnancy rate in clomiphene citrate, letrozole, or natural intrauterine insemination (IUI) cycles.

Higher ovulation rate with letrozole as compared with clomiphene citrate in infertile women with polycystic ovary syndrome: a systematic review and meta-analysis.

Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. According to the latest guidelines, letrozole should be considered as the first-line pharmacological treatment for women with WHO Group II anovulation or PCOS. However, the use of letrozole as an ovulation induction agent is not FDA or EMA approved, and its use is "off-label." The main concern with respect to letrozole regards its potential teratogenic effect on the fetus. To determine whether the probability of ovulation is higher with letrozole as compared to clomiphene citrate (CC) in anovulatory women with PCOS. Randomized controlled trials (RCTs) comparing letrozole versus CC used for ovulation induction in infertile women with PCOS followed by timed intercourse (TI) or intrauterine insemination (IUI) were included in this meta-analysis. Primary outcome was ovulation. Secondary outcomes were live birth, clinical pregnancy, miscarriage, multiple pregnancy, and congenital anomalies. Subgroup analysis included patients who received letrozole or CC as first-line treatment, and patients with PCOS diagnosed according to the Rotterdam criteria. Twenty-six RCTs published between 2006 and 2019, involving 4168 patients who underwent 8310 cycles of ovulation induction, were included. The probability of ovulation was significantly higher in letrozole as compared to CC cycles (RR: 1.148, 95% CI: 1.077 to 1.223, 3017 women, 19 trials, I2: 47.7%, low-quality evidence). A higher probability of ovulation is expected in infertile patients with PCOS treated with letrozole as compared to CC. The higher ovulation rate might have contributed to the higher clinical pregnancy and live birth rate. This finding is also true for patients who were administered letrozole as first-line treatment. CRD42019125166.

Response to ovulation induction treatments in women with polycystic ovary syndrome as a function of serum anti-Müllerian hormone levels.

To assess whether anti-Müllerian hormone (AMH) can predict response to ovulation induction (OI) with clomiphene citrate (CC), letrozole (LET), or follicle-stimulating hormone (FSH) in women with polycystic ovary syndrome (PCOS) undergoing OI/intrauterine inseminations (IUI). A total of 738 OI/IUI cycles from 242 patients at an academic center were stratified in three groups by medication: CC (n = 295), LET (n = 180), and FSH (n = 263), in a retrospective fashion. Ovarian response to treatment (RT, development of at least one dominant follicle) was assessed using mixed effects logistic regression models. Overall, RT cycles had lower AMH levels compared to no-RT cycles (p < 0.001). This finding persisted when analysis was limited to oral agents but attenuated in FSH cycles. For CC and LET cycles, the predicted probability (PProb) for RT decreased as AMH levels increased (PProb (95%CI): 97% (93-100), 79% (70-88), and 75% (61-89); 85% (78-93), 75% (67-83), and 73% (63-86) for AMH pct.: ≤ 25th, ≥ 50th, and ≥ 75th, for CC and LET, respectively)). However, RT was noted in 98.5% of FSH/IUI cycles regardless of AMH. For CC cycles, those with AMH ≥ 75th pct. had lower odds for RT over cycles with AMH < 75th pct. (OR 0.2, 95%CI 0.04-0.8, p = 0.02). Similarly, lower odds for RT were observed in LET cycles with AMH ≥ 75th pct. (0.6, 0.3-1.4, p = 0.25). In PCOS, increasing serum AMH levels are associated with lower probability of RT to oral agents. Our findings constitute a valuable tool for the clinician when counseling PCOS patients and designing a personalized ovulation induction treatment strategy.

Clarifying the relationship between total motile sperm counts and intrauterine insemination pregnancy rates

To study the relationship between postwash total motile sperm count (TMSC) and intrauterine insemination (IUI) outcomes. Retrospective review SETTING: Large fertility clinic PATIENT(S): A total of 92,471 insemination cycles from 37,553 patients were included in this study. All stimulated clomiphene citrate, letrozole, and/or injectable gonadotropin IUI cycles performed at a single institution from 2002 through 2018 were reviewed. Generalized estimating equations (GEE) analysis was used to account for multiple cycles by individual patients and to adjust for female partner age, body mass index, and stimulation protocol. Successful clinical pregnancy was defined as ultrasound confirmation of an intrauterine gestational sac with fetal cardiac activity. A total of 92,471 insemination cycles were available to evaluate the relationship between postwash TMSC and clinical pregnancy. Pregnancy rates were highest with TMSC of ≥9 × 106 and declined gradually as TMSC decreased. Complete data for the adjusted GEE analysis were available for 62,758 cycles. Adjusted GEE analysis among cycles with TMSC of ≥9 × 106 (n = 46,557) confirmed that TMSC in this range was unrelated to pregnancy. Conversely, TMSC was highly predictive of pregnancy (Wald χ2 = 39.85) in adjusted GEE analysis among cycles with TMSC of <9 × 106 (n = 16,201), with a statistically significant decline. IUI pregnancy is optimized with TMSC of ≥9 × 106, below which the rates gradually decline. Although rare, pregnancies were achieved with TMSC of <0.25 × 106. Since the decline in pregnancy is gradual and continuous, there is no specific threshold above which IUI should be recommended. Rather, these more specific quantitative predictions can be used to provide personalized counseling and guide clinical decision making.

Letrozole Versus Clomiphene Citrate and Natural Cycle: Endometrial Receptivity During Implantation Window in Women With Polycystic Ovary Syndrome.

ObjectiveNumerous studies have reported on ovulation and pregnancy rates in patients with polycystic ovary syndrome (PCOS). However, relevant data on endometrial receptivity are limited. This study was conducted to compare endometrial receptivity during implantation windows among letrozole (LE), clomiphene citrate (CC), and natural cycle, and to assess the predictive value for pregnancy of observed indicators.MethodsThis randomized controlled trial study enrolled 270 patients with PCOS. Patients were given LE (n=90) at a dose of 2.5mg/day or CC (n=90) at a dose of 50 mg/day on cycle days 5–9 for ovulation induction. Patients in the natural cycle group (n=90) did not receive any drug for ovulation induction. Endometrial ultrasonic parameters, integrin αvβ3, and vascular endothelial growth factor (VEGF) concentrations in uterine secretion were detected during the implantation window. The endometrial receptivity, ovulation rate, pregnancy rates, and predictive value of observed indicators for pregnancy were analyzed.ResultsThe successful ovulation rate did not differ between the LE group and CC group (P>0.05). Endometrial ultrasonic parameters [endometrial thickness (ET), endometrial volume (EV), vascularization index (VI), flow index (FI), vascularization flow index (VFI)], integrin αvβ3, and VEGF concentrations in uterine fluid were significantly higher in the LE group compared with the CC group and natural cycle group (P<0.05). The clinical pregnancy and ongoing pregnancy rates of the LE group were significantly higher than in the CC group (P<0.05). Endometrial ultrasonic parameters (VI, FI, and VFI), integrin αvβ3, and VEGF concentrations in uterine fluid of all pregnancy groups were significantly higher compared with the no pregnancy group (P<0.05), and the above parameters in ongoing pregnancy were significantly higher than in biochemical pregnancy (P<0.05). The endometrial FI during the implantation window had the highest predictive value for pregnancy (AUC=0.889). The integrin αvβ3 in uterine fluid had better predictive value (AUC=0.876) than VEGF.ConclusionsEndometrial receptivity during the implantation window of LE is superior to CC in PCOS women, which may be related to higher clinical pregnancy and ongoing pregnancy rates. Endometrial FI examined by 3-D power Doppler, and integrin αvβ3 in uterine secretion during the implantation window, could be preferable non-invasive predictor markers for pregnancy.Clinical Trial Registration www.chictr.org.cn, ChiCTR1900023423.

Women's Reports of Barriers to and Facilitators of Oral Medication Adherence During Ovarian Stimulation: A Mixed Methods Pilot Study.

Background:Adherence to lifestyle modification recommendations remains problematic for women undergoing fertility treatment, raising concerns about the extent to which women adhere to prescribed medication regimens. Limited data have shown suboptimal oral medication adherence rates of 19% to 74%. The objective of this study was to explore what women perceive as barriers to and facilitators of oral medication adherence during fertility treatment cycles.Methods:An exploratory mixed methods pilot study was conducted among a sample of 30 women who were actively taking one to two cycles of letrozole or clomiphene citrate for ovarian stimulation in conjunction with intrauterine insemination cycles. Medication adherence barriers were measured using a 20-item survey. Medication adherence facilitators and personal experiences with fertility treatment were assessed with structured interviews. Medication adherence was assessed with electronic event monitoring.Results:The overall medication adherence median was 0.97 with a range of 0.75 to 1.00, and nine women (50%) demonstrated perfect adherence. The most commonly reported barriers were recently feeling sad, down, or blue (53%), and taking medication more than once per day (40%). Women with higher barrier scores had significantly lower medication adherence scores (p=0.02) compared to women with lower total barrier scores. Facilitators included using physical aides as reminders (60%) and establishing a daily routine (50%). No significant correlation was found between medication adherence scores and facilitators.Conclusion:The dynamic interplay between perceived barriers and facilitators and women’s medication-taking patterns could influence whether or not medication regimens are followed correctly.

Optimal lead follicle size for human chorionic gonadotropin trigger in clomiphene citrate and intrauterine insemination cycles: an analysis of 1,676 treatment cycles

To identify the optimal lead follicle size for hCG trigger in clomiphene citrate (CC)-intrauterine insemination (IUI) cycles. Retrospective cohort study. University-affiliated center. Patients <40 years of age with ovulatory dysfunction or unexplained infertility undergoing their first CC-IUI cycle. Ovulation induction, hCG trigger, and IUI. Clinical pregnancy rate (CPR) was the primary outcome and was plotted against lead follicle size in increments of 1 mm. Odds ratios with 95% confidence intervals for associations between lead follicle size and CPR were calculated from a multivariable logistic regression model. A receiver operating characteristic (ROC) curve was generated for CPR as a function of lead follicle size. 1,676 cycles were included. The overall CPR was 13.8% (232/1,676). There was no difference in baseline demographics or ovulation induction parameters of patients who did or did not conceive. The odds of clinical pregnancy were 2.3 and 2.2 times higher with lead follicle sizes of 21.1-22.0 mm and >22.0 mm, respectively, compared with the referent category of 19.1-20.0 mm. Lead follicle size was an independent predictor of CPR, even after accounting for confounders. A lead follicle size of 22.1 mm corresponded to a sensitivity and specificity of 80.1% and 90.4% for clinical pregnancy, respectively, with an area under the ROC curve of 0.89. hCG administration at a lead follicle size of 21.1-22.0 mm is associated with higher odds of clinical pregnancy in patients undergoing their first CC-IUI cycles for ovulatory dysfunction or unexplained infertility.

Clomiphene Citrate versus Recombinant FSH in intrauterine insemination cycles with mono- or bi-follicular development.

Objective:The present study aims to assess the success of controlled ovarian stimulation in intrauterine insemination cycles stimulated by recombinant-FSH and Clomiphene citrate for either mono- or bi-follicular development.Methods:We assessed 870 infertile patients treated with controlled ovarian stimulation in intrauterine insemination cycles at a university-based infertility clinic between January 2012 and December 2017. We compared the cycles stimulated by clomiphene citrate and recombinant-FSH in two set-ups; mono- and bi-follicular development. The main outcome measure was the clinical pregnancy rate per cycle.Results:The demographic and cycle parameters were similar between the groups, except for endometrial thickness on the day of hCG administration, which was higher in the recombinant-FSH group than the clomiphene citrate group. The overall clinical pregnancy rates in clomiphene citrate and recombinant-FSH groups were 9.8% and 10.3%, respectively (p=0.940). Regarding the entire cohort, clinical pregnancy was significantly higher in cases of bi-follicular development when compared to mono-follicular development (16.8% vs. 10.2%, respectively; p=0.009).Conclusions:Clomiphene citrate and recombinant-FSH have similar success rates in terms of clinical pregnancy, in either mono-follicular development or bi-follicular development. Clomiphene citrate and recombinant-FSH cycles resulted in comparable rates of bi-follicular development, which significantly increases clinical pregnancy rate. Clomiphene citrate and recombinant-FSH have similar success rates in terms of clinical pregnancy, in either mono-follicular development or bi-follicular development.

Short-term weight change and live birth among women with unexplained infertility and polycystic ovary syndrome undergoing ovulation induction

To determine if short-term weight change among women with unexplained infertility (UI) and polycystic ovary syndrome (PCOS) undergoing ovulation induction is associated with live birth. Secondary analysis of randomized trials. Multicenter fertility trial sites. A total of 900 women with UI and 750 women with PCOS. Live birth. Weight assessment at enrollment and start of up to 4-5 cycles of clomiphene, letrozole, or gonadotropins and intrauterine insemination for women with UI and clomiphene or letrozole with regular intercourse for women with PCOS. Weight data were available for 856 women with UI and 697 women with PCOS. Mean weight change was -0.2 ± 0.3 kg among women with UI and +2.2 ± 0.2 kg among women with PCOS and did not differ based on treatment allocation. There were 115 women with PCOS (16.4%) who gained ≥3 kg. Increased body mass index and three or more cycles were associated with weight gain in women with PCOS. There was no difference in live birth rate among women with PCOS and ≥3 kg weight gain and women with PCOS who did not gain weight. Women with PCOS gained an average of 2.2 kg regardless of the medication received, whereas women with UI experienced no short-term weight change during ovulation induction. Weight gain in women with PCOS was not associated with live birth rate.

Impact of Luteal phase clomiphene citrate on endometrial thickness and clinical pregnancy rates in women with polycystic ovary syndrome

Objective: To compare between luteal phase clomiphene citrate and second cycle day clomiphene citrate on the thickness of the endometrium and clinical pregnancy rates in women with polycystic ovary syndrome. Methods: a prospective observational study conducted on 196 women with Polycystic ovary syndrome divided into two groups: Group 1 (98 patients) received 100mg of clomiphene citrate daily for 5 days starting on second cycle day and Group 2 (98 patients) received 100mg of clomiphene citrate daily starting in the luteal phase before onset of withdrawal bleeding for 5 days. Treatment and follow up applied for three cycles. Outcome measures were collected and analyzed and women who got pregnant were followed until 12 weeks of pregnancy. Results: no significant differences between the two groups regarding pre-ovulatory endometrial thickness (8.3mm in group 1vs 8.8mm in group 2), number of mature follicles (1.62 in group 1vs 1.57 in group 2) and mid-luteal serum progesterone levels(14.63ng/ml in group 1vs 14.9ng/ml in group 2). 34 women (35%) got pregnant in group 1 and 37 women (38%) in-group 2 and three patients had miscarriage in each group without any statistical significance. Conclusion: the present study does not support luteal clomiphene citrate over second cycle day clomiphene citrate to induce ovulation in infertile women with polycystic ovary syndrome.

Success Rates of Clomiphene Citrate and Recombinant Gonadotropin Cycles: A Single-Center Experience

Objective: This aim of this study is to assess the ovulation induction cycles based on clomiphene citrate and gonadotropin administration and specify the factors associated with successful outcomes. Study Design: This is a prospective study of 631 patients who underwent 917 ovulation induction cycles. While clomiphene citrate was used in 680 cycles (74.2%) and recombinant follicle-stimulating hormone was administered in 237 cycles (25.8%). Results: A total of 153 pregnancies were achieved in 917 ovulation induction cycles, indicating a clinical pregnancy rate of 16.7%. The ovulation induction cycles which ended up with clinical pregnancy had a significantly lower frequency of smoking (p=0.005), shorter infertility duration (p=0.001), higher basal luteinizing hormone (p=0.021) and lower basal progesterone (p=0.008) than unsuccessful cycles. The clomiphene citrate cycles which ended up with clinical pregnancy had a significantly lower frequency of smoking (p=0.011), shorter infertility duration (p=0.001) and lower basal progesterone (p=0.013) than the unsuccessful cycles. The recombinant follicle-stimulating hormone cycles which ended up with clinical pregnancy had a significantly higher basal luteinizing hormone (p=0.008) than the unsuccessful cycles. Basal luteinizing hormone and progesterone concentrations could significantly distinguish the patients who were able to conceive in ovulation induction cycles (p=0.021 and p=0.008, respectively).Conclusions: Smoking, longer duration of infertility, and elevated basal progesterone are poor prognostic factors for clinical pregnancy in clomiphene citrate and recombinant follicle-stimulating hormone cycles.

Ovulation Rate after Metformin and Clomiphene vs Clomiphene Alone in Polycystic Ovary Syndrome (PCOS): A Randomized, Double-Blind, Placebo-Controlled Trial

Background: Polycystic ovary syndrome (PCOS) affects 5%-15% of women of reproductive age and has a negative impact on their fertility. The primary outcome of this study is ovulation rate when standard (immediate release) metformin (MF) is added to clomiphene citrate (CC) in oligoovulatory and anovulatory women with PCOS. Methods: This is a randomized, double-blind, placebo-controlled trial. Twenty-seven women with PCOS (according to the Rotterdam consensus), desiring pregnancy and without another cause of subfertility were recruited from a public hospital outpatient gynecology clinic. Up to six cycles of CC (25-150 mg) plus either MF 500 mg tds (CC+MF) or placebo (CC+Pl) were offered. Student’s t-test, Chi-squared test, and Fisher’s exact test were used for analysis. Results: Thirteen women with up to six cycles each were included in the final analysis. The rate of ovulation and ovulation rate per cycle was similar between women in the CC+MF and CC+Pl groups RR 1.09 (95% CI 0.80-1.49) and RR 0.88 (95% CI 0.63-1.22), respectively as was chemical pregnancy rate RR 1.77 (95% CI 0.58-5.38). The live birth rate was higher in CC+MF RR 6.83 (95% CI 0.83-56.27) and miscarriage rate was lower RR 0.21 (95% CI 0.002-1.07). The number needed to treat for live birth was 10. Conclusion: Use of standard MF, 500 mg tds, when given with CC results in an increase in live birth rate, and a decrease in miscarriage rate.

Changes in serum markers of patients with PCOS during consecutive clomiphene stimulation cycles: a retrospective study

BackgroundA retrospective case-control study was performed to evaluate whether PCOS-specific serum markers would change in women with polycystic ovary syndrome (PCOS) during the course of two consecutive cycles of clomiphene citrate (CC)-stimulation, which did not lead to a pregnancy.MethodsAnovulatory PCOS patients who underwent two consecutive CC-cycles (n = 41) and anovulatory PCOS controls who chose an observational approach for two months (n = 24) were included in the study. The main outcome measures were levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH), total testosterone, androstenedione, and sexual hormone binding globulin (SHBG).ResultsIn the control group, PCOS-specific serum parameters did not change during two months (p > 0.05). In the CC-group, there were decreases in LH (11.8 ± 4.9 mU/mL vs. 10.9 ± 4.0 mU/mL; p = 0.029), the LH:FSH ratio (2.1 ± 0.8 mU/mL vs. 1.8 ± 0.5 mU/mL; p = 0.007), and AMH (8.08 ± 4.27 ng/mL vs. 7.17 ± 3.37 ng/mL; p = 0.011), as well as an increase in SHBG (46.0 ± 20.2 nmol/L vs. 51.2 ± 21.0 nmol/L; p < 0.001). A higher age and lower baseline total testosterone and AMH levels were predictive of an AMH decline (p < 0.05).ConclusionTwo cycles of CC-stimulation that did not lead to a pregnancy were accompanied by mean LH, AMH, and LH:FSH ratio declines and an SHBG increase. The clinical significance seems of minor relevance.