Risk factors for poor oocyte yield and oocyte immaturity after GnRH agonist triggering.

STUDY QUESTION: What are the potential risk factors for poor oocyte recuperation rate (ORR) and oocyte immaturity after GnRH agonist (GnRHa) ovulation triggering? SUMMARY ANSWER: Lower ovarian reserve and LH levels after GnRHa triggering are risk factors of poor ORR. Higher BMI and anti-Müllerian hormone (AMH) levels are risk factors of poor oocyte maturation rate (OMR). WHAT IS KNOWN ALREADY: The use of GnRHa to trigger ovulation is increasing. However, some patients may have a suboptimal response after GnRHa triggering. This suboptimal response can refer to any negative endpoint, such as suboptimal oocyte recovery, oocyte immaturity, or empty follicle syndrome. For some authors, a suboptimal response to GnRHa triggering refers to a suboptimal LH and/or progesterone level following triggering. Several studies have investigated a combination of demographic, clinical, and endocrine characteristics at different stages of the treatment process that may affect the efficacy of the GnRHa trigger and thus be involved in a poor endocrine response or efficiency but no consensus exists. STUDY DESIGN, SIZE, DURATION: Bicentric retrospective cohort study between 2015 and 2021 (N = 1747). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients aged 18-43 years who underwent controlled ovarian hyperstimulation and ovulation triggering by GnRHa alone (triptorelin 0.2 mg) for ICSI or oocyte cryopreservation were included. The ORR was defined as the ratio of the total number of retrieved oocytes to the number of follicles >12 mm on the day of triggering. The OMR was defined as the ratio of the number of mature oocytes to the number of retrieved oocytes. A logistic regression model with a backward selection method was used for the analysis of risk factors. Odds ratios (OR) are displayed with their two-sided 95% confidence interval. MAIN RESULTS AND THE ROLE OF CHANCE: In the multivariate analysis, initial antral follicular count and LH level 12-h post-triggering were negatively associated with poor ORR (i.e. below the 10th percentile) (OR: 0.61 [95% CI: 0.42-0.88]; P = 0.008 and OR: 0.86 [95% CI: 0.76-0.97]; P = 0.02, respectively). A nonlinear relationship was found between LH level 12-h post-triggering and poor ORR, but no LH threshold was found. A total of 25.3% of patients suffered from oocyte immaturity (i.e. OMR < 75%). In the multivariate analysis, BMI and AMH levels were negatively associated with an OMR < 75% (OR: 4.34 [95% CI: 1.96-9.6]; P < 0.001 and OR: 1.22 [95% CI: 1.03-1.12]; P = 0.015, respectively). Antigonadotrophic pretreatment decreased the risk of OMR < 75% compared to no pretreatment (OR: 0.72 [95% CI: 0.57-0.91]; P = 0.02). LIMITATIONS, REASONS FOR CAUTION: Our study is limited by its retrospective design and by the exclusion of patients who had hCG retriggers. However, this occurred in only six cycles. We were also not able to collect information on the duration of pretreatment and the duration of wash out period. WIDER IMPLICATIONS OF THE FINDINGS: In clinical practice, to avoid poor ORR, GnRHa trigger alone should not be considered in patients with higher BMI and/or low ovarian reserve, balanced by the risk of ovarian hyperstimulation syndrome. In the case of a low 12-h post-triggering LH level, practicians must be aware of the risk of poor ORR, and hCG retriggering could be considered. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

GnRH agonist pretreatment for frozen embryo transfer among women with polycystic ovary syndrome: a narrow systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Frozen embryo transfer (FET) is usually recommended for women with polycystic ovary syndrome (PCOS) undergoing In vitro fertilization (IVF). While there is no consensus as to the optimal protocol of endometrial preparation for FET. The effect of gonadotropin-releasing hormone agonist (GnRH-a) pretreatment for FET among women with PCOS remains controversial. PURPOSE: We intend to explore whether GnRH-a pretreatment could improve clinical outcomes for women with PCOS undergoing FET. METHODS: PubMed, Embase, ClinicalTrials.gov, Cochrane Library, and Web of Science were searched up to May 16, 2024. Eligible studies involved patients with PCOS undergoing FET and receiving GnRH-a pretreatment for endometrial preparation, with artificial cycle (AC) as the control therapy. Only randomized controlled trials (RCTs) published in Chinese and English were included. Data extraction was performed independently by two authors. Effect was quantified using odd ratios (ORs) with 95% confidence intervals (CIs) using random-effect models with the Mantel-Hansel (M-H) method in Revman software. Quality of outcomes was evaluated using the GRADEpro system. Primary outcomes contained the clinical pregnancy rate, miscarriage rate, and live birth rate. Secondary outcomes included the incidence of preterm labor and gestational diabetes mellitus (GDM). RESULTS: Ninety-seven records were initially retrieved, with 21 duplicates and 65 articles excluded after title and abstract screening. Seven studies were excluded due to retrospective design, leaving three RCTs with 709 participants. Among them, 353 received GnRH-a pretreatment as the intervention group and 356 received AC as the control group. No significant differences were observed in the clinical pregnancy rate (OR 1.09, 95% CI 0.75 to 1.56, P = 0.66), miscarriage rate (OR 0.73, 95% CI 0.28 to 1.90, P = 0.52), live birth rate (OR 0.87, 95% CI 0.61 to 1.25, P = 0.46), and the risk of preterm labor (OR 1.45, 95% CI 0.79 to 2.65, P = 0.23) and GDM (OR 0.73, 95% CI 0.37 to 1.48, P = 0.39) between the two groups. CONCLUSIONS: In this meta-analysis, GnRH-a pretreatment does not confer any advantages and appears unnecessary for women with PCOS undergoing FET. Additional RCTs should focus on maternal complications and the health of offspring.

Risk of borderline ovarian tumors after fertility treatment - Results from a Danish cohort of infertile women.

OBJECTIVE: Results from previous studies examining the association between fertility treatment and borderline ovarian tumors are inconsistent. The aim of this study was to investigate the association between fertility treatment and borderline ovarian tumors in a cohort of infertile women. METHODS: This cohort study was based on the Danish Infertility Cohort and included all infertile women aged 20-45 years living in Denmark between 1 January 1995 and 31 December 2017 (n = 146,891). Information on use of fertility drugs, borderline ovarian tumors and cancer diagnoses, covariates, emigration, and vital status was obtained by linkage to national registers. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) with adjustment for potential confounders for overall borderline ovarian tumors and for serous- and mucinous borderline ovarian tumors separately. RESULTS: During a median 11.3 years of follow-up, 144 women developed a borderline ovarian tumor. No marked associations between ever use of clomiphene citrate, gonadotropins, gonadotropin-releasing hormone receptor modulators, human chorionic gonadotropin or progesterone and borderline ovarian tumors were observed, neither overall nor for serous and mucinous borderline ovarian tumors analysed separately. Further, no clear associations with borderline ovarian tumors were found according to cumulative dose, time since first use or parity status for any fertility drugs. CONCLUSIONS: No marked associations between use of fertility drugs and borderline ovarian tumors were observed. However, the cohort's relatively young age at end of follow-up emphasizes the importance of extending the follow-up period for women who have used fertility drugs.

GnRH agonist trigger in poor prognosis patients undergoing a multicycle approach through DuoStim or consecutive stimulations: a SWOT analysis.

PURPOSE OF REVIEW: Identify the most recent and significant evidence regarding the ovulation trigger within the framework of a multicycle approach through DuoStim, providing valuable insights for improving treatment strategies in patients with a poor prognosis. RECENT FINDINGS: The trigger method plays a pivotal role in optimizing in-vitro fertilization (IVF) stimulation, influencing oocyte retrieval and maturation rates, as well as follicle recruitment in consecutive ovarian stimulations such as double stimulation. Decision-making involves multiple factors and, while guidelines exist for conventional stimulation, specific recommendations for the multicycle approach are not well established. SUMMARY: The different methods for inducing oocyte maturation underscore the need for personalization of IVF protocols. The GnRH agonist trigger induces rapid luteolysis and establishes favorable hormonal conditions that do not adversely affect the recruitment of consecutive follicular waves in the context of DuoStim. It serves as a valid alternative to hCG in freeze-all cycles. This strategy might enhance the safety and flexibility of ovarian stimulations with no impact on oocyte competence and IVF efficacy.

A meta-analysis of efficacy on dexamethasone and clomiphene in the treatment of polycystic ovary syndrome patients.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is an endocrine gynecological disease affecting many women of reproductive age. Clomiphene is the first-line treatment for PCOS patients, but most individuals may be resistant to it. This study aims to assess the efficacy of dexamethasone and clomiphene in the treatment of PCOS patients, and to provide a theoretical basis for clinicians to study and treat PCOS. METHODS: Chinese and English databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang Medical Network, and VIP Information Chinese Journal Service Platform (VIP) were searched from the inception to January 2023. Review Manager and Stata software were used for meta- analysis. The risk of bias of eligible studies were assessed using Cochrane's risk of bias tool. Publication bias was assessed by funnel plots, Begg's and Egger's tests. RESULTS: A total of 12 literatures were finally included, with a total of 1270 PCOS patients. Compared with the control group, dexamethasone combined with clomiphene could significantly improve pregnancy (RR = 1.71, P < 0.00001), ovulation (RR = 1.30, P < 0.00001), luteinizing hormone level (SMD = -0.94, P < 0.00001), estradiol level (SMD = 0.99, P = 0.05), progesterone level (SMD = 5.08, P = 0.002) and testosterone level (SMD = -1.59, P < 0.00001). However, there were no significant effects on ovulation-stimulating hormone level (SMD = 0.15, P = 0.37), adverse reactions (RR = 1.30, P = 0.30), dizziness (RR = 1.50, P = 0.45), and vomiting (RR = 1.67, P = 0.48). CONCLUSION: The treatment of dexamethasone combined with clomiphene is helpful to improve the ovulation and pregnancy rate in patients with PCOS, and improve the hormone levels of patients.

Is combined letrozole and clomiphene superior to either as monotherapy: a systemic review and meta-analysis based on clinical trials.

OBJECTIVE: This research was conducted to assess the therapeutic advantage of combined letrozole and clomiphene citrate versus monotherapy for polycystic ovarian syndrome (PCOS) patients. STUDY DESIGN: Five databases were searched using the search string: (letrozole and clomiphene) AND (clomiphene OR clomiphene citrate OR CC) AND (letrozole OR LE) AND (ovulation induc* OR fertility induc* OR fertility preserv*) AND (polycystic ovarian syndrome OR PCOS). All statistical analyses were conducted in Review Manager 5.4.1. Random effect-effect model was used to pool risk ratio (RR), mean difference (MD), and odds ratio (OR) and their corresponding 95% confidence interval (CI). Moreover, qualitative analysis was conducted to qualitatively analyze ovulation, secondary outcomes, and cycle characteristics. RESULTS: One clinical trial and three randomized clinical trials (RCTs) were used in the study. Two studies were used in a quantitative analysis showing that combination was superior for ovulation induction (RR = 1.86 [1.37, 2.53]; p < 0.0001; I2 = 0%), but the number of follicles ≥15 mm was significantly associated with the combination (MD = 0.40[0.14, 0.66]; p = 0.002; I2 = 0%). On subgroup analysis, only hot flushes were significantly associated with the combination (RR = 2.67[1.12, 6.36]; p = 0.03; I2 = 0%). The meta-analysis of two studies reported a significantly higher ovulation rate and number of dominant follicles in the combination therapy group compared with the LE alone arm but no significant difference in pregnancy rate, endometrial thickness, and adverse events. CONCLUSION: Our study demonstrates a significant effect of the combination on ovulation induction. The combination yielded a better chance of conception and viable pregnancy. Further studies are needed to determine the live birth rate. HighlightsCombined Letrozole and Clomiphene is superior to either of these drugs alone for ovulation induction in PCOS.Our results conclude that the combination results in better ovulation, cycle characteristics, and secondary changes.Only the incidence of hot flushes as an adverse effect is increasingly reported in combination.

Competence of Combined Low Dose of Human Chorionic Gonadotropin (HCG) and Clomiphene Citrate (CC) Versus Continued CC during Ovulation Induction in Women with CC-Resistant Polycystic Ovarian Syndrome: A Randomized Controlled Trial.

Background and Objectives: Polycystic ovarian syndrome (PCOS) is a widespread endocrine disorder affecting 5-18% of females in their childbearing age. The aim of this study is to assess the efficacy of combining a low dosage of human chorionic gonadotropin (HCG) along with clomiphene citrate (CC) for stimulating ovulation in infertile women diagnosed with CC-resistant PCOS. Materials and Methods: A randomized controlled trial was carried out on 300 infertile CC-resistant PCOS women. All participants were assigned to two groups: the CC-HCG group and the CC-Placebo group. Subjects in the CC-HCG group were given CC (150 mg/day for 5 days starting on the 2nd day of the cycle) and HCG (200 IU/day SC starting on the 7th day of the cycle). Subjects in the CC-Placebo group were given CC and a placebo. The number of ovarian follicles > 18 mm, cycle cancellation rate, endometrial thickness, ovulation rate, clinical pregnancy rate, and occurrence of early ovarian hyper-stimulation syndrome were all outcome variables in the primary research. Results: Data from 138 individuals in the CC-HCG group and 131 participants in the CC-Placebo group were subjected to final analysis. In comparison to the CC-Placebo group, the cycle cancellation rate in the CC-HCG group was considerably lower. The CC-HCG group exhibited a substantial increase in ovarian follicles reaching > 18 mm, endometrial thickness, and ovulation rate. The clinical pregnancy rate was higher in the CC-HCG group (7.2% vs. 2.3%; CC-HCG vs. CC-Placebo). Upon adjusting for BMI and age, the findings of our study revealed that individuals in the CC-HCG group who had serum prolactin levels below 20 (ng/mL), secondary infertility, infertility duration less than 4 years, baseline LH/FSH ratios below 1.5, and serum AMH levels more than 4 (ng/mL) had a higher likelihood of achieving pregnancy. In the CC-Placebo group, there was a greater prediction of clinical pregnancy for those with serum AMH (<4), primary infertility, serum prolactin ≤ 20 (ng/mL), baseline LH/FSH < 1.5, and infertility duration < 4 years. Conclusions: The use of a small dose of HCG along with CC appeared to be an effective treatment in reducing cycle cancelation, improving the clinical pregnancy rate and ovulation rate in CC-resistant PCOS patients. The trial was registered with Clinical Trials.gov, identifier NCT02436226.

Benefit from luteal phase progestin primed ovarian stimulation with clomiphene citrate supplementation in young women with diminished ovarian reserve: a retrospective study. / å¹´è½»åµå·¢å‚¨å¤‡åŠŸèƒ½å‡é€€æ‚£è€ åµæ³¡æœŸä¸Žé»„ä½“æœŸåº”ç”¨é«˜å­•æ¿€ç´ çŠ¶æ€è¶ ä¿ƒæŽ’åµæ–¹æ¡ˆæ•ˆæžœæ¯”è¾ƒ.

OBJECTIVES: To compare the pregnancy outcomes of luteal phase and follicular phase progestin-primed ovarian stimulation protocol with clomiphene citrate supplementation (LPPOS+CC and FPPOS+CC) in young women with diminished ovarian reserve (DOR). METHODS: A total of 483 women aged ≤35 years with DOR, who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)/embryo transfer (ET) with controlled ovarian stimulation using LPPOS+CC (n=257) or FPPOS+CC (n=226) protocols during June 2018 and December 2021 at the First Affiliated Hospital of Wenzhou Medical University, were included in this retrospective study. The baseline characteristics, superovulation results, laboratory related indicators between the two groups, and the pregnancy outcomes of women who achieved at least one high-quality cleavage-stage embryo or good-morphology blastocyst were compared between the two groups. RESULTS: No statistically significant differences were identified between the groups with respect to age, duration of infertility, proportion of secondary infertility, previous failed cycles, body mass index, anti-Müllerian hormone, antral follicle count, basal luteinizing hormone level, basal progesterone level, number of oocytes retrieved, oocyte maturation rate, high-quality cleavage-stage embryo cycle rate, the percentage of women with profound pituitary suppression, live birth rate and preterm birth rate (all P>0.05). The LH levels on the day of trigger [4.0 (2.7, 5.3) vs. 5.1 (3.2, 7.2) IU/L], the percentage of women with LH levels of >10 IU/L on the trigger day (3.13% vs. 10.67%), and the two pronucleus (2PN) rate of ICSI oocytes (72.16% vs. 79.56%) were significantly lower in the LPPOS+CC group than those in the FPPOS+CC group (P<0.05 or P<0.01). The duration of stimulation [11 (9, 12) vs. 9 (8, 11) d], the consumption of total gonadotropin [2213 (1650, 2700) vs. 2000 (1575, 2325) IU], the progesterone levels on the day of trigger [1.3 (0.8, 2.9) vs. 0.9 (0.6, 1.2) ng/mL], the clinical pregnancy rate [61.88% vs. 46.84%], and implantation rate [42.20% vs. 31.07%] in the LPPOS+CC group were significantly higher than those in the FPPOS+CC group (all P<0.01). CONCLUSIONS: Compared to FPPOS+CC, the LPPOS+CC protocol appears to have better pregnancy outcomes for young women with DOR undergoing IVF/ICSI-ET.

Predictors of response to ovulation induction using letrozole in women with polycystic ovary syndrome.

BACKGROUND: This study aimed to evaluate the predictive value of the initial screening characteristics of women with anovulatory polycystic ovary syndrome (PCOS) who did or did not respond to 2.5 mg letrozole (LET). METHODS: The clinical and laboratory characteristics of women with PCOS who underwent LET treatment were evaluated. Women with PCOS were stratified according to their responses to LET (2.5 mg). The potential predictors of their responses to LET were estimated using logistic regression analysis. RESULTS: Our retrospective study included 214 eligible patients with a response to 2.5 mg LET (n = 131) or no response to 2.5 mg LET (n = 83). PCOS patients who responded to 2.5 mg LET showed better outcomes than those who did not (2.5 mg LET) for pregnancy rate, live birth rate, pregnancy rate per patient, and live birth rate per patient. Logistic regression analyses showed that late menarche (odds ratio [OR], 1.79 [95% confidence intervals (CI), 1.22-2.64], P = 0.003), and increased anti-müllerian hormone (AMH) (OR, 1.12 [95% CI, 1.02-1.23], P = 0.02), baseline luteinizing hormone (LH)/ follicle stimulating hormone (FSH) (OR, 3.73 [95% CI, 2.12-6.64], P < 0.001), and free androgen index (FAI) (OR, 1.37 [95% CI, 1.16-1.64], P < 0.001) were associated with a higher possibility of no response to 2.5 mg LET. CONCLUSIONS: PCOS patients with an increased LH/FSH ratio, AMH, FAI, and late menarche may need an increased dosage of LET for a treatment response, which could be helpful in designing a personalized treatment strategy.

Trends in clomiphene citrate and gonadotropins use in women with infertility between 2010 and 2017: A population-based study in France.

PURPOSE: To describe temporal trends and assess factors associated with changes in the prescription of clomiphene citrate and gonadotropins between 2010 and 2017 in women with infertility aged 18-50 from metropolitan France. METHODS: 6321 prevalent women from a representative sample of the national medico-administrative database were identified. We performed a Cochran-Armitage trend test and calculated the rate ratios. A Poisson regression was used to derive the incidence rate ratios, for each treatment class. RESULTS: The prevalence rate and incidence rate of clomiphene citrate use significantly decreased by 20% (RR 0.80: 95% CI 0.71-0.90) and 23% (RR 0.77: 95% CI 0.66-0.89), respectively. Its initiation was higher in all age groups compared to the reference (18-24 years), with a downward gradient. It was also higher when the density of gynaecologists was higher and in disadvantaged areas. The prevalence rate and incidence rate of gonadotropin use increased by 11% (RR 1.11: 95% CI 1.01-1.22) and 33% (RR 1.33: 95% CI 1.14-1.55) respectively. Gonadotropin initiation was highest in the 31-35 age group, but it was also higher in the 25-30 and 36-40 age groups at a similar level (reference 18-24 years). Its initiation was higher when the density of gynaecologists was higher, but not associated with social deprivation. CONCLUSION: Our results showed an increase in gonadotropin use for infertility treatment in France during the 2010-2017 period and a decrease in clomiphene citrate use. Further work should be undertaken to analyse the use of these drugs in relation to women's care pathways.

In vitro fertilisation for unexplained subfertility.

BACKGROUND: In vitro fertilisation (IVF) is a treatment for unexplained subfertility but is invasive, expensive, and associated with risks. OBJECTIVES: To evaluate the effectiveness and safety of IVF versus expectant management, unstimulated intrauterine insemination (IUI), and IUI with ovarian stimulation using gonadotropins, clomiphene citrate (CC), or letrozole in improving pregnancy outcomes. SEARCH METHODS: We searched following databases from inception to November 2021, with no language restriction: Cochrane Gynaecology and Fertility Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL. We searched reference lists of articles and conference abstracts. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing effectiveness of IVF for unexplained subfertility with expectant management, unstimulated IUI, and stimulated IUI. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. MAIN RESULTS: IVF versus expectant management (two RCTs) We are uncertain whether IVF improves live birth rate (LBR) and clinical pregnancy rate (CPR) compared to expectant management (odds ratio (OR) 22.0, 95% confidence interval (CI) 2.56 to 189.37; 1 RCT; 51 women; very low-quality evidence; OR 3.24, 95% CI 1.07 to 9.8; 2 RCTs; 86 women; I2 = 80%; very low-quality evidence). Adverse effects were not reported. Assuming 4% LBR and 12% CPR with expectant management, these would be 8.8% to 9% and 13% to 58% with IVF. IVF versus unstimulated IUI (two RCTs) IVF may improve LBR compared to unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12; 2 RCTs; 156 women; I2 = 60%; low-quality evidence). We are uncertain whether there is a difference between IVF and IUI for multiple pregnancy rate (MPR) (OR 1.03, 95% CI 0.04 to 27.29; 1 RCT; 43 women; very low-quality evidence) and miscarriage rate (OR 1.72, 95% CI 0.14 to 21.25; 1 RCT; 43 women; very low-quality evidence). No study reported ovarian hyperstimulation syndrome (OHSS). Assuming 16% LBR, 3% MPR, and 6% miscarriage rate with unstimulated IUI, these outcomes would be 18.5% to 49%, 0.1% to 46%, and 0.9% to 58% with IVF. IVF versus IUI + ovarian stimulation with gonadotropins (6 RCTs), CC (1 RCT), or letrozole (no RCTs) Stratified analysis was based on pretreatment status. Treatment-naive women There may be little or no difference in LBR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.19, 95% CI 0.87 to 1.61; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 1.63, 95% CI 0.91 to 2.92; 2 RCTs; 221 women; I2 = 54%; low-quality evidence); or between IVF and IUI + CC (OR 2.51, 95% CI 0.96 to 6.55; 1 RCT; 103 women; low-quality evidence). Assuming 42% LBR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 26% LBR with IUI + gonadotropins (1 IVF to 1 IUI cycle), LBR would be 39% to 54% and 24% to 51% with IVF. Assuming 15% LBR with IUI + CC, LBR would be 15% to 54% with IVF. There may be little or no difference in CPR between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 1.17, 95% CI 0.85 to 1.59; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 4.59, 95% CI 1.86 to 11.35; 1 RCT; 103 women; low-quality evidence); or between IVF and IUI + CC (OR 3.58, 95% CI 1.51 to 8.49; 1 RCT; 103 women; low-quality evidence). Assuming 48% CPR with IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles) and 17% with IUI + gonadotropins (1 IVF to 1 IUI cycle), CPR would be 44% to 60% and 28% to 70% with IVF. Assuming 21% CPR with IUI + CC, CPR would be 29% to 69% with IVF. There may be little or no difference in multiple pregnancy rate (MPR) between IVF and IUI + gonadotropins (1 IVF to 2 to 3 IUI cycles: OR 0.82, 95% CI 0.38 to 1.77; 3 RCTs; 731 women; I2 = 0%; low-quality evidence; 1 IVF to 1 IUI cycle: OR 0.76, 95% CI 0.36 to 1.58; 2 RCTs; 221 women; I2 = 0%; low-quality evidence); or between IVF and IUI + CC (OR 0.64, 95% CI 0.17 to 2.41; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in OHSS between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 6.86, 95% CI 0.35 to 134.59; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference in OHSS with 1 IVF to 1 IUI cycle (OR 1.22, 95% CI 0.36 to 4.16; 2 RCTs; 221 women; I2 = 0%; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.53, 95% CI 0.24 to 9.57; 1 RCT; 102 women; low-quality evidence). We are uncertain if there is a difference in miscarriage rate between IVF and IUI + gonadotropins with 1 IVF to 2 to 3 IUI cycles (OR 0.31, 95% CI 0.03 to 3.04; 1 RCT; 207 women; very low-quality evidence); and there may be little or no difference with 1 IVF to 1 IUI cycle (OR 1.16, 95% CI 0.44 to 3.02; 1 RCT; 103 women; low-quality evidence). There may be little or no difference between IVF and IUI + CC (OR 1.48, 95% CI 0.54 to 4.05; 1 RCT; 102 women; low-quality evidence). In women pretreated with IUI + CC IVF may improve LBR compared with IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57; 1 RCT; 280 women; low-quality evidence). Assuming 22% LBR with IUI + gonadotropins, LBR would be 39% to 65% with IVF. IVF may improve CPR compared with IUI + gonadotropins (OR 14.13, 95% CI 7.57 to 26.38; 1 RCT; 280 women; low-quality evidence). Assuming 30% CPR with IUI + gonadotropins, CPR would be 76% to 92% with IVF. AUTHORS' CONCLUSIONS: IVF may improve LBR over unstimulated IUI. Data should be interpreted with caution as overall evidence quality was low.

Clomiphene citrate plus letrozole versus clomiphene citrate alone for ovulation induction in infertile women with ovulatory dysfunction: a randomized controlled trial.

BACKGROUND: The aim of this study was to compare the efficacy of the combination of clomiphene citrate (CC) and letrozole to that of CC alone in inducing ovulation in infertile women with ovulatory dysfunction. METHODS: A randomized controlled trial was conducted at a single academic medical center between November 2020 and December 2021. Anovulatory infertility females, aged 18 to 40, were evenly distributed by a computer-generated block of four into two treatment groups. A "combination group" received a daily dose of CC (50 mg) and letrozole (2.5 mg), while a "CC-alone group" received a daily dose of CC alone (50 mg). The study medications were administered on days 3 through 7 of menstrual cycle. The primary outcome was the ovulation rate, defined by serum progesterone levels exceeding 3 ng/mL at the mid-luteal phase. The secondary outcomes were ovulation induction cycle characteristics, endometrial thickness, conception rate, and adverse events. RESULTS: One hundred women (50 per group) were enrolled in the study. The mean age was not significantly different in both groups: 31.8 years in the combination group and 32.4 years in the CC-alone groups (P = 0.54). The prevalence of polycystic ovary syndrome in the combination and CC-alone groups was 48% and 44%, respectively (P = 0.841). According to intention-to-treat analysis, the ovulation rates were 78% and 70% in the combination and CC-alone groups, respectively (P > 0.05). There was no significant difference in the mean endometrial thickness or the number of dominant follicles of the groups. No serious adverse events were observed in either group. CONCLUSIONS: Our study found no significant difference between the combination of CC and letrozole and CC alone in inducing ovulation in infertile women with ovulatory dysfunction in one cycle. The small number of live births precluded any meaningful statistical analysis. Further studies are needed to validate and extend our findings beyond the scope of the current study. TRIAL REGISTRATION: The study was registered at https://www.thaiclinicaltrials.org with the following number: TCTR20201108004 and was approved on 08/11/2020.

Ovulation induction with letrozole and dexamethasone in infertile patients with letrozole-resistant polycystic ovary syndrome.

PURPOSE: To assess efficacy of adjuvant dexamethasone during letrozole cycles for ovulation induction (OI) in women with letrozole-resistant polycystic ovary syndrome (PCOS). METHODS: We retrospectively evaluated 42 cycles of OI from 28 infertile women with letrozole-resistant PCOS between September 2019 and November 2022. Letrozole was initiated on cycle day 3 for 5 days and increased via a stair-step approach to 7.5 mg as indicated. Patients were deemed letrozole-resistant if no dominant follicle was identified on transvaginal ultrasound following this dose. Resistant patients then received 5 additional days of letrozole 7.5 mg with low-dose dexamethasone 0.5 mg for 7 days and had a repeat ultrasound. The primary outcome was ovulation rate determined by the presence of a dominant follicle on ultrasound. Secondary outcomes included endometrial thickness, number of measurable follicles, and pregnancy outcomes among responders. RESULTS: Twenty-two of 28 (79%) letrozole-resistant PCOS patients had evidence of ovulation after the addition of dexamethasone in 35 out of 42 (83%) cycles. Clinical pregnancy occurred in 20% of ovulatory cycles with a cumulative rate of 32%. All clinical pregnancies resulted in a live birth. Patients who responded to adjuvant dexamethasone were more likely to have a shorter duration of infertility; however, there were no differences in other demographics, serum androgens including DHEA-S, or pretreatment glycemic status. CONCLUSION: Adding dexamethasone to letrozole increased ovulation rates in letrozole-resistant PCOS patients undergoing OI with similar pregnancy outcomes to prior studies. The addition of dexamethasone is an effective, inexpensive, and safe option for PCOS patients otherwise at risk for cycle cancelation.

Comparative Study Of Combined Co-Enzyme Q10 And Clomiphene Citrate Vs Clomiphene Citrate Alone For Ovulation Induction In Patients With Polycystic Ovarian Syndrome.

A total of 136 patients with PCOS were followed through the Department of the Obstetrics and Gynaecology, Unit-IV, Lady Aitchison Hospital, Lahore. Patients were randomly divided by lottery method into two groups i.e., Group-A (CoQ10 plus Clomiphene citrate) and Group-B (Clomiphene citrate alone). The selected patients in the study group (group-A) were given Clomiphene citrate 100mg/day from cycle days 2-6 for 45 days (2 cycles) and CoQ10 in a dose of 50mg soft gel capsules thrice per day starting at cycle day-2, until HCG administration. Patients in controlled group (group 21 B) received Clomiphene citrate 100mg/day twice a day cycle for 45 days. Data were analysed in SPSS v25.0. In group-A (CoQ10 plus Clomiphene citrate), successful ovulation induction was noted in 16 (23.5%) patients, showing that with the addition of CoQ10, the chances of ovulation induction increased.

Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction.

STUDY QUESTION: What are the comparative pregnancy outcomes in women who receive up to six consecutive cycles of ovulation induction with letrozole versus clomiphene citrate? SUMMARY ANSWER: The risks of pregnancy, livebirth, multiple gestation, preterm birth, neonatal intensive care unit (NICU) admission and congenital malformations were higher for letrozole compared with clomiphene in participants with polycystic ovarian syndrome (PCOS), though no treatment differences were observed in those with unexplained infertility. WHAT IS KNOWN ALREADY: Randomized trials have reported higher pregnancy and livebirth rates for letrozole versus clomiphene among individuals with PCOS, but no differences among those with unexplained infertility. None of these trials were designed to study maternal or neonatal complications. STUDY DESIGN, SIZE, DURATION: We emulated a hypothetical trial of the comparative effectiveness of letrozole versus clomiphene citrate for ovulation induction among all women, then stratified by PCOS and unexplained infertility status. We used real-world data from a large healthcare claims database in the USA (2011-2015). PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed data from 18 120 women who initiated letrozole and 49 647 women who initiated clomiphene during 2011-2014, and who were aged 18-45 years with no history of diabetes, thyroid disease, liver disease or breast cancer and had no fertility treatments for 3 months before trial initiation. The treatment strategies were clomiphene citrate or letrozole for six consecutive cycles. The outcomes were pregnancy, livebirth, multiple gestation, preterm birth, small for gestational age (SGA), NICU admission and major congenital malformations. We estimated the probability of each outcome under each strategy via pooled logistic regression and used standardization to adjust for confounding and selection bias due to loss to follow-up. MAIN RESULTS AND THE ROLE OF CHANCE: The estimated probabilities of pregnancy, livebirth and neonatal outcomes were similar under each strategy, both overall and among individuals with unexplained infertility. Among women with PCOS, the probability of pregnancy was 43% for letrozole vs 37% for clomiphene (risk difference [RD] = 6.0%; 95% CI: 4.4, 7.7) in the intention-to-treat analyses. The corresponding probability of livebirth was 32% vs 29% (RD = 3.1%; 95% CI: 1.5, 4.8). In per protocol analyses, the risk of multiple gestation was 19% vs 9%, the risk of preterm birth was 20% vs 15%, the risk of SGA was 5% vs 3%, the risk of NICU admission was 22% vs 16% and the risk of congenital malformation was 8% vs 2% among those with a livebirth. LIMITATIONS, REASONS FOR CAUTION: We cannot completely rule out the possibility of residual confounding by body mass index or duration of infertility. However, we adjusted for proxies identified in administrative data and results did not change. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that for women with unexplained infertility, the two treatments result in comparable probabilities of a livebirth. For women with PCOS, letrozole appears slightly more effective for attaining a livebirth. Neonatal outcomes were similar for the two treatments among women with unexplained infertility; we did not confirm the hypothesized higher risk of adverse neonatal outcomes for clomiphene versus letrozole. The risks of adverse neonatal outcomes were slightly greater among women with PCOS who were treated with letrozole versus clomiphene. It is likely that these effects are partially mediated through an increased risk of multiple gestation among women who received letrozole. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institute of Child Health and Human Development (R01HD088393). Y.-H.C. reports grants from the American Heart Association (834106) and NIH (R01HD097778). P.R. reports grants from the National Institutes of Health. J.H. reports grants from the National Institutes of Health, the Agency for Healthcare Research and Quality, and the California Health Care Foundation during the conduct of the study; and consulting for several health care delivery organizations including Cambridge Health Alliance, Columbia University, University of Southern California, Community Servings, and the Delta Health Alliance. S.H.-D. reports grants from the National Institutes of Health and the US Food and Drug Administration during the conduct of the study; grants to her institution from Takeda outside the submitted work; consulting for UCB (biopharmaceutical company) and Roche; and being an adviser for the Antipsychotics Pregnancy Registry and epidemiologist for the North American Antiepileptics Pregnancy Registry, both at Massachusetts General Hospital. M.A.H. reports grants from the National Institutes of Health and the U.S. Veterans Administration during the conduct of the study; being a consultant for Cytel; and being an adviser for ProPublica. TRIAL REGISTRATION NUMBER: N/A.

Gonadotropin-releasing hormone agonist downregulation combined with hormone replacement therapy improves the reproductive outcome in frozen-thawed embryo transfer cycles for patients of advanced reproductive age with idiopathic recurrent implantation failure.

BACKGROUND: To determine whether gonadotropin-releasing hormone (GnRH) agonist downregulation combined with hormone replacement therapy (HRT) can improve the reproductive outcomes in frozen-thawed embryo transfer cycles for older patients (aged 36-43 years) with idiopathic recurrent implantation failure (RIF). METHODS: This retrospective cohort study involved 549 older patients undergoing their third cleavage-stage embryo or blastocyst transfer over a 5-year period (January 2015-December 2020) at Northwest Women's and Children's Hospital after in vitro fertilization/intracytoplasmic sperm injection cycles. Patients with known endometriosis or adenomyosis were excluded from the study. The patients were divided into three groups according to the endometrial preparation protocol: the natural cycle (NC) group (n = 65), the HRT group (n = 194), and the GnRH agonist downregulation combined with HRT cycle (GnRH agonist-HRT) group (n = 290). The primary outcome was the live birth rate, and the secondary outcomes were the clinical pregnancy, miscarriage, and ongoing pregnancy rates. RESULTS: The live birth rate in the GnRH agonist-HRT group (36.55%) was higher than that in the HRT group (22.16%) and NC group (16.92%) (P < 0.0001). Similarly, a logistic regression model adjusting for potential confounders showed that the live birth rate was higher in the GnRH agonist-HRT group than in the HRT group (odds ratio, 0.594; 95% confidence interval, 0.381-0.926; P = 0.021) and NC group (odds ratio, 0.380; 95% confidence interval, 0.181-0.796; P = 0.010). CONCLUSIONS: The GnRH agonist-HRT protocol improves the live birth rate in frozen-thawed embryo transfer cycles for patients of advanced reproductive age with RIF. We hypothesize that the GnRH agonist-HRT protocol enhances implantation-related factors and promotes optimal endometrial receptivity, leading to an improved live birth rate. These findings are also useful for further investigating the underlying mechanism of the GnRH agonist-HRT protocol in improving the reproductive outcomes for patients of advanced reproductive age with RIF. TRIAL REGISTRATION: This research protocol was approved by the hospital institutional ethics committee (No. 2021002).

Evaluation of an alternative heterotopic transplantation model for ovarian tissue to test pharmaceuticals improvements for fertility restoration.

BACKGROUND: Ovarian tissue cryopreservation and transplantation (OTCTP) is currently the main option available to preserve fertility in prepubertal patients undergoing aggressive cancer therapy treatments. However, a major limitation of OTCTP is follicle loss after transplantation. The mouse is a model of choice for studying ovarian function and follicle development after ovarian tissue grafting in vivo. In these mouse models, ovarian tissue or ovaries can be transplanted to different sites. Our aim was to evaluate a new alternative to heterotopic transplantation models that could be useful to test pharmaceutical improvement for ovarian grafts after OTCTP. METHODS: Slow frozen murine whole ovaries were transplanted into the mouse ears (between the external ear skin layer and the cartilage). Ovarian transplants were recovered after 3, 14 or 21 days. Grafts were analyzed by immunohistochemistry and follicle density analyses were performed. RESULTS: An increase of ovarian vascularization (CD31 and Dextran-FITC positive staining), as well as cellular proliferation (Ki67 staining) were observed 3 weeks after transplantation in comparison to 3 days. Fibrosis density, evaluated after Van Gieson staining, decreased 3 weeks after transplantation. Furthermore, transplantation of cryopreserved ovaries into ovariectomized mice favored follicle activation compared to transplantation into non-ovariectomized mice. CONCLUSION: The present study indicates that surgical tissue insertion in the highly vascularized murine ear is an effective model for ovarian grafting. This model could be helpful in research to test pharmaceutical strategies to improve the function and survival of cryopreserved and transplanted ovarian tissue.

Transcriptome analysis of eutopic endometrium in adenomyosis after GnRH agonist treatment.

BACKGROUND: Adenomyosis is a chronic gynecological disease characterized by invasion of the uterine endometrium into the muscle layer. In assisted reproductive technology (ART), gonadotropin-releasing hormone agonist (GnRHa) is often used to improve pregnancy rates in patients with adenomyosis, but the underlying mechanisms are poorly understood. METHODS: Eutopic endometrial specimens were collected from patients with adenomyosis before and after GnRHa treatment in the midsecretory phase. RNA sequencing (RNA-Seq) of these specimens was performed for transcriptome analysis. The differentially expressed genes (DEGs) of interest were confirmed by real-time PCR and immunohistochemistry. RESULTS: A total of 132 DEGs were identified in the endometrium of patients with adenomyosis after GnRHa treatment compared with the control group. Bioinformatics analysis predicted that immune system-associated signal transduction changed significantly after GnRHa treatment. Chemokine (C-C motif) ligand 21 (CCL21) was found to be highly expressed in the eutopic endometrium after GnRHa treatment, which may be involved in the improvement of endometrial receptivity in adenomyosis. CONCLUSION: This study suggests that molecular regulation related to immune system-associated signal transduction is an important mechanism of GnRHa treatment in adenomyosis. Immunoreactive CCL21 is thought to regulate inflammatory events and participate in endometrial receptivity in adenomyosis.

The influence of ethnicity on outcomes of ovulation induction with clomifene citrate in women with PCOS.

RESEARCH QUESTION: What is the influence of ethnicity on the outcome of ovulation induction with clomifene citrate in women with polycystic ovary syndrome (PCOS)? DESIGN: This was a retrospective cohort study. In total, 420 women diagnosed with PCOS who were of Northern European, Mediterranean, African, South-East Asian or South American descent, and who started ovulation induction treatment with clomifene citrate, were included. All women were treated with clomifene citrate according to a standardized treatment regimen. The minimal effective dose of clomifene citrate and prevalence of clomifene resistance (CRA) were assessed, and the chance of becoming ovulatory was predicted. RESULTS: Differences were observed in body mass index (P = 0.008), waist circumference (P = 0.036) and serum LH, insulin and androgen concentrations (all P < 0.001) in women of different ethnicities with PCOS. Compared with women of Northern European descent, the minimal effective dose of clomifene citrate in women of other ethnic groups was not significantly different. The prevalence of CRA (P = 0.574) was similar in all ethnic groups A similar chance of ovulation (P = 0.504) was predicted for the different ethnic groups. CONCLUSIONS: This is the first study aiming to link ethnicity to ovulation induction outcome in PCOS. Although women of different ethnicities who have PCOS exhibit a variation in phenotypic expression, there do not appear to be differences in the prevalence of clomifene-resistant anovulation or the minimal effective dose of clomifene citrate. Furthermore, a prediction model revealed no significant differences in the predicted chance of ovulation. A larger cohort is needed to validate these findings.

Metformin, clomiphene citrate and flutamide effects on oocyte ultrastructure status and quality in PCOS mouse model.

RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) alters oocyte developmental competence and so the treatment of PCOS patients with assisted reproductive techniques is a major challenge for an infertility specialist. Does ovulation induction therapy with clomiphene citrate, metformin and flutamide affect abnormal PCOS follicle gene expression, its quality, and nuclear and cytoplasmic maturation in the oocyte matured in vitro? DESIGN: Fifty NMRI mice (7-8 weeks old) were randomly divided into five groups, including non-PCOS, PCOS and PCOS groups treated with clomiphene citrate (18 mg/kg body weight for 2 days), metformin (50 mg/100 g body weight for 30 days) and flutamide (10 mg/kg body weight injection for 15 days). The oocytes were collected for quantitative real-time polymerase chain reaction analysis (the evaluation of genes associated with oocyte maturation), transmission electron microscopy (the evaluation of cytoplasmic maturation) and in-vitro maturation (IVM) and IVF outcomes. RESULTS: The dysregulated expression of some genes of insulin-like growth factor (IGF) families involved in oocyte competence and steroid metabolism (e.g. Cyp19a1 and Cyp11a1), transforming growth factor beta (TGF-ß) family (e.g. Tgfb1, Gdf9, Bmp15, Inhbb and Bmpr1a), and oestrogen receptor signalling (e.g. Ncoa3, Pgr) was, to some extent, restored in the PCOS follicles following their with clomiphene citrate, metformin and flutamide. The improved cytoplasmic maturation was observed particularly in the PCOS mice treated with clomiphene citrate. The better IVM-IVF outcomes were also observed in the clomiphene citrate and metformin groups compared with the PCOS group. CONCLUSIONS: This study opens up a new perspective on knowing the effect of ovulation induction therapy on not only nuclear maturation but also ultrastructural characteristics, IVM-IVF outcomes and PCOS oocyte developmental competence.