Updates to Male Infertility: AUA/ASRM Guideline (2024).

PURPOSE: In 2023 the American Urological Association (AUA) requested an Update Literature Review (ULR) to incorporate new evidence generated since the 2020 publication of this Guideline. The resulting 2024 Guideline Amendment addresses updated recommendations to provide guidance on the appropriate evaluation and management of the male partner in an infertile couple. MATERIALS AND METHODS: In 2023, the Male Infertility Guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines. An updated literature search identified 4093 new abstracts. Following initial abstract screening, 125 eligible study abstracts met inclusion criteria. On data extraction, 22 studies of interest were included in the final evidence base to inform the Guideline amendment. RESULTS: The Panel developed evidence- and consensus-based statements based on an updated review to provide guidance on evaluation and management of male infertility. These updates are detailed herein. CONCLUSIONS: This update provides several new insights, including revised thresholds for Y-chromosome microdeletion testing, indications for pelvic MRI imaging in infertile males, and guidance regarding the use of testicular sperm in nonazoospermic males. This Guideline will require further review as the diagnostic and treatment options in this space continue to evolve.

Effect of prematurely elevated late follicular progesterone on pregnancy outcomes following ovarian stimulation-intrauterine insemination for unexplained infertility: secondary analysis of the AMIGOS trial.

STUDY QUESTION: What is the relationship between late follicular phase progesterone levels and clinic pregnancy and live birth rates in couples with unexplained infertility undergoing ovarian stimulation with IUI (OS-IUI)? SUMMARY ANSWER: Late follicular progesterone levels between 1.0 and <1.5 ng/ml were associated with higher live birth and clinical pregnancy rates while the outcomes in groups with higher progesterone levels did not differ appreciably from the <1.0 ng/ml reference group. WHAT IS KNOWN ALREADY: Elevated late follicular progesterone levels have been associated with lower live birth rates after fresh embryo transfer following controlled ovarian stimulation and egg retrieval, but less is known about whether an association exists with outcomes in OS-IUI cycles. Existing studies are few and have been limited to ovarian stimulation with gonadotrophins, but the use of oral agents, such as clomiphene citrate and letrozole, is common with these treatments and has not been well studied. STUDY DESIGN, SIZE, DURATION: The study was a prospective cohort analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) randomized controlled trial. Frozen serum was available for evaluation from 2121 cycles in 828 AMIGOS participants. The primary pregnancy outcome was live birth per cycle, and the secondary pregnancy outcome was clinical pregnancy rate per cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples with unexplained infertility in the AMIGOS trial, for whom female serum from day of trigger with hCG was available in at least one cycle of treatment, were included. Stored frozen serum samples from day of hCG trigger during treatment with OS-IUI were evaluated for serum progesterone level. Progesterone level <1.0 ng/ml was the reference group for comparison with progesterone categorized in increments of 0.5 ng/ml up to ≥3.0 ng/ml. Unadjusted and adjusted risk ratios (RR) and 95% CI were estimated using cluster-weighted generalized estimating equations to estimate modified Poisson regression models with robust standard errors. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to the reference group with 110/1363 live births (8.07%), live birth rates were significantly increased in cycles with progesterone 1.0 to <1.5 ng/ml (49/401 live births, 12.22%) in both the unadjusted (RR 1.56, 95% CI 1.14, 2.13) and treatment-adjusted models (RR 1.51, 95% CI 1.10, 2.06). Clinical pregnancy rates were also higher in this group (55/401 clinical pregnancies, 13.72%) compared to reference group with 130/1363 (9.54%) (unadjusted RR 1.46, 95% CI 1.10, 1.94 and adjusted RR 1.42, 95% CI 1.07, 1.89). In cycles with progesterone 1.5 ng/ml and above, there was no evidence of a difference in clinical pregnancy or live birth rates relative to the reference group. This pattern remained when stratified by ovarian stimulation treatment group but was only statistically significant in letrozole cycles. LIMITATIONS, REASONS FOR CAUTION: The AMIGOS trial was not designed to answer this clinical question, and with small numbers in some progesterone categories our analyses were underpowered to detect differences between some groups. Inclusion of cycles with progesterone values above 3.0 ng/ml may have included those wherein ovulation had already occurred at the time the IUI was performed. These cycles would be expected to experience a lower success rate but pregnancy may have occurred with intercourse in the same cycle. WIDER IMPLICATIONS OF THE FINDINGS: Compared to previous literature focusing primarily on OS-IUI cycles using gonadotrophins, these data include patients using oral agents and therefore may be generalizable to the wider population of infertility patients undergoing IUI treatments. Because live births were significantly higher when progesterone ranged from 1.0 to <1.5 ng/ml, further study is needed to clarify whether this progesterone range may truly represent a prognostic indicator in OS-IUI cycles. STUDY FUNDING/COMPETING INTEREST(S): Oklahoma Shared Clinical and Translational Resources (U54GM104938) National Institute of General Medical Sciences (NIGMS). AMIGOS was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, and U10HD055925. Research made possible by the funding by American Recovery and Reinvestment Act. Dr Burks has disclosed that she is a member of the Board of Directors of the Pacific Coast Reproductive Society. Dr Hansen has disclosed that he is the recipient of NIH grants unrelated to the present work, and contracts with Ferring International Pharmascience Center US and with May Health unrelated to the present work, as well as consulting fees with May Health also unrelated to the present work. Dr Diamond has disclosed that he is a stockholder and a member of the Board of Directors of Advanced Reproductive Care, Inc., and that he has a patent pending for the administration of progesterone to trigger ovulation. Dr Anderson, Dr Gavrizi, and Dr Peck do not have conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Effect of small follicles on clinical pregnancy and multiple pregnancy rates in intrauterine insemination: a cohort study.

STUDY QUESTION: What is the effect of small follicles on clinical pregnancy and multiple pregnancy rates in women undergoing IUI with ovarian stimulation (IUI-OS)? SUMMARY ANSWER: The presence of ≥2 small follicles with a diameter of 10-12 or 12-14 mm was associated with an increased chance of clinical pregnancy and the presence of any 12-14 mm or larger follicles, but not smaller follicles, was statistically significantly associated with an increased risk for multiple pregnancy. WHAT IS KNOWN ALREADY: IUI-OS is widely used as the first-line treatment for unexplained or mild male factor infertility. However, IUI is associated with the risk of multiple pregnancy. While the positive association between the number of follicles ≥14 mm and the chance of pregnancy and the risk of multiple pregnancy is known, the impact of smaller follicles is uncertain. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study that included women undergoing IUI cycles from January 2007 to May 2021 in one assisted reproduction center. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied the impact of the number and size of follicles on trigger day on clinical pregnancy and multiple pregnancy rates. Generalized estimation equation regression models were used to compute unadjusted and adjusted odds ratios and 95% CI in all women and only women who achieved clinical pregnancy separately. The chance of clinical pregnancy and multiple pregnancy for different numbers of small follicles in cycles with one >18-mm follicle was calculated using marginal effects estimate. MAIN RESULTS AND THE ROLE OF CHANCE: This cohort included 12 933 IUI cycles in 7504 women. The overall clinical pregnancy rate was 16.1% (2081/12 933), with a multiple pregnancy rate of 10.5% (218/2081). In the adjusted analysis, the chance of clinical pregnancy increased significantly with the increase in the number of follicles with the diameter of 14-16, 16-18, and 18-20 mm. As for 10-12 mm [adjusted odds ratio (aOR) 1.22, 95% CI 1.02-1.46] and 12-14 mm (aOR 1.29, 95% CI 1.07-1.56) follicles, only groups with ≥2 follicles of those sizes showed significantly increased chance of clinical pregnancy. In cycles that led to pregnancy, follicles with the diameter of 12-14 mm were associated with an increased risk of multiple pregnancy (aOR 1.73, 95% CI 1.19-2.53 for one such follicle; aOR 2.27, 95% CI 1.44-3.56 for ≥2 such follicles), while 10- to 12-mm follicles were not significantly associated with multiple pregnancy (aOR 1.18, 95% CI 0.72-1.95 for ≥2 such follicles). The associations of multiple pregnancy were similar when including all cycles. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective observational study from a single center. The records of follicle diameter in our center were of a 2-mm interval which limited our ability to analyze the size of follicle as a continuous variable. Also, the number of cycles with a high number of small follicles was still limited which impeded more detailed analysis on the ≥2 follicles subgroup. Similarly, the value of some parts of the marginal probability estimation for multiple pregnancy versus pregnancy according to size and number of follicles was also limited by the low sample size of certain combinations. WIDER IMPLICATIONS OF THE FINDINGS: Follicles larger than 10 mm, especially those ≥12 mm, may need to be clearly recorded during transvaginal ultrasound surveillance and their potential effects on both pregnancy and multiple pregnancy can be discussed with couples undergoing IUI. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (Grant numbers 82201912, 82371651, and 82071615) and Shanghai Sailing Program (21YF1423200). B.W.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.M. reports consultancy for ObsEva and Merck and travel support from Merck. B.W.M. has received research funding from Ferring and Merck. The authors declare no other competing interests. TRIAL REGISTRATION NUMBER: N/A.

Luteal phase support with oral progesterone improves live birth rate in intrauterine insemination cycles using letrozole.

RESEARCH QUESTION: Does luteal phase support (LPS) with oral progesterone improve the live birth rate (LBR) in patients undergoing intrauterine insemination (IUI) cycles with letrozole? DESIGN: This retrospective cohort study included 1199 IUI cycles with letrozole between January 2017 and December 2021. A nearest neighbour random matching approach was employed to pair the LPS group and the control group in a 1:2 ratio. Eight variables were chosen for matching in the propensity score matching (PSM) model: age; body mass index; duration of infertility; cause(s) of infertility; antral follicle count; basal concentration of FSH; rank of IUI attempts; and leading follicle size. LBR was selected as the primary outcome. RESULTS: In total, 427 LPS cycles were matched with 772 non-LPS (control) cycles after PSM. The LBR was significantly higher in the LPS group compared with the control group (19.7% versus 14.5%; P = 0.0255). The clinical pregnancy rate (23.2% versus 17.6%; P = 0.0245) and ongoing pregnancy rate (20.6% versus 15.8%; P = 0.0437) were also significantly higher in the LPS group. The biochemical pregnancy rate, ectopic pregnancy rate and miscarriage rate were similar in the two groups (P > 0.05). The intergroup comparison revealed no significant variances in terms of gestational age, mode of delivery, ectopic pregnancy rate or abortion rate. Furthermore, there were no significant differences in birth weight or birth length between the two groups. CONCLUSIONS: Luteal support with oral progesterone significantly improved the LBR in IUI cycles with letrozole, but did not affect neonatal outcomes.

A prospective proof-of-concept trial on the effect of personalized dosages of follitropin delta in intrauterine insemination.

RESEARCH QUESTION: What is the efficacy and safety of individualized follitropin delta dosing for ovarian stimulation in intrauterine insemination (IUI)? DESIGN: This single-centre, prospective, open-label, single-cohort study involving 106 patients established an original dosing regimen based on body weight and anti-Müllerian hormone (AMH) concentrations, with adjustments based on the ovarian response from the previous IUI cycle. Each participant was enrolled in a maximum of three IUI cycles. RESULTS: Mean age was 34.5 ± 4.5 years, mean weight 69.2 ± 11.2 kg, mean AMH 15.7 ± 8.6 pmol/l, mean FSH 6.3 ± 2.6 IU/l and mean antral follicle count 16.4 ± 8.2. The percentage of patients who produced more than three mature follicles was 1.9%, 0% and 1.5%, respectively, for the three IUI cycles. The percentage of patients with two or three mature follicles was 34.0%, 36.9% and 47.1% for the three IUI cycles. The clinical pregnancy rate per IUI cycle was 17.9%, 14.3% and 17.6% for the three cycles, with a cumulative clinical pregnancy rate of 40.6%. Out of 258 cycles, 43 (16.7%) resulted in clinical pregnancy, with six of those resulting in multiple pregnancies (14.0%). Two resulted in spontaneous reduction within the first trimester and four resulted in live twin births, representing only 1.6% of the total cycles. CONCLUSIONS: This study is the first to utilize follitropin delta for stimulation in IUI. It demonstrates that individualized dosing is both effective and safe, resulting in satisfactory cumulative pregnancy rates and an acceptable multiple pregnancy rate, thus achieving the primary objectives of the research.

The relationship between duration of infertility and clinical outcomes of intrauterine insemination for younger women: a retrospective clinical study.

BACKGROUND: The objective of this research was to elucidate the association between the length of infertility and the outcomes of intrauterine insemination (IUI) in women of varying ages - a topic that has been the subject of investigation for numerous years, yet lacks a definitive consensus. METHODS: A retrospective cohort investigation involving 5268 IUI cycles was undertaken at the Reproductive Medicine Center of Nanjing Drum Tower Hospital from 2016 to 2022. Utilizing the smooth fitting curve along with threshold and saturation effect analysis, the correlation between infertility duration and IUI clinical pregnancy rates was discerned. Moreover, patients were bifurcated into two cohorts based on their respective infertility durations. A secondary examination was also performed employing propensity-score matching to mitigate the impact of confounding variables. Subsequent threshold and saturation effect analysis was carried out across various subgroups, segmented on the basis of age differentiation. RESULTS: When the duration of infertility was more than 5 years, the clinical pregnancy rate decreased with the increase of infertility duration (aOR: 0.894, 95%CI: 0.817-0.991, p = 0.043). The multivariate regression analysis suggested that longer duration of infertility (≥ 5 years) was significantly correlated with the lower clinical pregnancy rate (aOR: 0.782, 95% CI: 0.643-0.950, p = 0.01). After the propensity-score matching, the clinical pregnancy rate of women with longer infertility duration were also higher. When the duration of infertility was more than 5 years, the clinical pregnancy rate of women younger than 35 years old decreased with the increase of infertility duration (aOR: 0.906, 95%CI: 0.800-0.998, p = 0.043). CONCLUSIONS: The clinical pregnancy rate and live birth rate of IUI in young women (< 35 years old) who have been infertile for more than 5 years significantly decrease with the prolongation of infertility time. Therefore, for young women who have been infertile for more than 5 years, IUI may not be the best choice.

Analysis of factors associated with IUI pregnancy outcomes in elderly and young patients.

OBJECTIVE: The objective of this study was to investigate the correlation between various factors and the clinical outcomes of Intrauterine Insemination (IUI) in both young and aged patients, aiming to provide a theoretical basis for clinical consultations. METHODS: This retrospective analysis examined a total of 4,221 IUI cycles conducted at the Reproductive Center of Changzhou Maternal and Child Health Hospital between January 2016 and December 2020. The patients were categorized into two groups based on age: the elder group (≥ 35 years) and the young group (< 35 years). RESULTS: The findings of this study revealed a significant association between woman's age and BMI with pregnancy outcomes (0.93, 95% CI: 0.89-0.97) (1.04, 95% CI: 1.01-1.06). Moreover, in young women, both age and Body Mass Index (BMI)were found to be related to pregnancy outcomes (0.97, 95% CI: 0.89-0.97) (1.08, 95% CI: 1.01-1.06). Additionally, BMI and the number of cycles in aged IUI patients were found to be associated with pregnancy outcomes. The pregnancy rate in the second cycle was approximately 1.9 times higher than that in the first cycle (1.9, 95% CI: 0.97-3.77), and in the third cycle, it was approximately 3 times higher than that in the first cycle (3.04, 95% CI: 1.43-6.42). CONCLUSIONS: In conclusion, there is an association between woman's age and BMI and the clinical outcomes of IUI. However, the number of cycles did not affect the pregnancy outcomes in young women. Conversely, in elder women, the number of cycles was found to be related to the IUI pregnancy outcomes, with significantly higher pregnancy rates observed in the second and third cycles compared to the first cycle.

Optimizing timing for intrauterine insemination (IUI) in donor sperm cycles: pre- versus post-ovulation insemination in natural cycles.

PURPOSE: To investigate whether pregnancy outcomes of natural cycle intrauterine insemination (IUI) with donor sperm can be improved by performing insemination after confirmation of ovulation. METHODS: This retrospective cohort study evaluated 751 couples undergoing 1170 cycles of artificial insemination with donor sperm (AID) in natural cycles between January 2018 and January 2021. Patients underwent AID either within 6-12 h after spontaneous luteinizing hormone (LH) surge (pre-ovulation group) or after ovulation was confirmed by ultrasound (post-ovulation group). Propensity score matching was performed to account for differences in baseline characteristics between groups. The main outcome measures of this study were clinical pregnancy rate and live birth rate. RESULTS: After propensity score matching, each group comprised 216 cycles. No significant differences were observed between the pre-ovulation and post-ovulation groups in terms of clinical pregnancy rate (30.6% vs 27.3%, respectively, p = .458) and live birth rate (25.0% vs 22.7%, respectively, p = .651). However, upon excluding cases of luteinized unruptured follicle syndrome (LUFS) from the pre-ovulation group, the clinical pregnancy rate (33.5% vs 27.3%, respectively, p = .043) and live birth rate (27.4% vs 22.7%, respectively, p = .039) were significantly higher in the pre-ovulation group. CONCLUSIONS: For fertile women undergoing AID in natural cycles, pre-ovulation insemination timing yielded superior pregnancy outcomes compared to post-ovulation insemination when ovulation was achieved. However, due to the occurrence of LUFS, pre- and post-ovulation AID resulted in comparable overall pregnancy outcomes in natural cycles.

Rescue intrauterine insemination in women failing to retrieve oocytes at ovum pick-up: report of a case series.

PURPOSE: Failure to collect oocytes at the time of oocyte pick-up is an unfavorable outcome of in vitro fertilization (IVF) cycles. In these cases, prompt intrauterine insemination (IUI) could be an option (rescue IUI), but this possibility has been poorly studied. METHODS: Rescue IUI is routinely offered in our unit in women failing to retrieve oocytes, provided that they have at least one patent tube, normal male semen analysis, and the total number of developed follicles is ≤ 3. We therefore reviewed all oocyte retrievals performed from 2006 to 2022 in our unit to identify these cases. As a comparator, we referred to preplanned IUI performed during the same study period. The 95% confidence interval (95% CI) of proportions was calculated using a binomial distribution model. RESULTS: Rescue IUI was performed in 96 out of 3531 oocyte retrievals (2.7%; 95% CI 2.2-3.3%). Six live births were obtained, corresponding to 6.2% (95% CI 2.3-13.1). All pregnancies were singletons. CONCLUSIONS: Rescue IUI in women failing to retrieve oocytes is a possible option that may be considered in selected cases. The efficacy is low, but the procedure is simple, and without significant risks. Generalizability to a conventional IVF protocol setting is however limited.

Development of a machine learning-based prediction model for clinical pregnancy of intrauterine insemination in a large Chinese population.

PURPOSE: This study aimed to evaluate the effectiveness of a random forest (RF) model in predicting clinical pregnancy outcomes from intrauterine insemination (IUI) and identifying significant factors affecting IUI pregnancy in a large Chinese population. METHODS: RESULTS: A total of 11 variables, including eight from female (age, body mass index, duration of infertility, prior miscarriage, and spontaneous abortion), hormone levels (anti-Müllerian hormone, follicle-stimulating hormone, luteinizing hormone), and three from male (smoking, semen volume, and sperm concentration), were identified as the significant variables associated with IUI clinical pregnancy in our Chinese dataset. The RF-based prediction model presents an area under the receiver operating characteristic curve (AUC) of 0.716 (95% confidence interval, 0.6914-0.7406), an accuracy rate of 0.6081, a sensitivity rate of 0.7113, and a specificity rate of 0.505. Importance analysis indicated that semen volume was the most vital variable in predicting IUI clinical pregnancy. CONCLUSIONS: The machine learning-based IUI clinical pregnancy prediction model showed a promising predictive efficacy that could provide a potent tool to guide selecting targeted infertile couples beneficial from IUI treatment, and also identify which parameters are most relevant in IUI clinical pregnancy.

Anti-Müllerian hormone does not predict cumulative pregnancy rate in non-infertile women following four IUI cycles with donor sperm.

PURPOSE: To evaluate the predictive value of serum AMH for clinical pregnancy in non-infertile population undergoing intrauterine insemination with donor sperm (ds-IUI). METHODS: This multicenter prospective study (ClinicalTrials.gov ID: NCT06263192) recruited all non-infertile women undergoing ds-IUI from June 2020 to December 2022 in three different fertility clinics in Spain and Chile. Indications for ds-IUI included severe oligoasthenoteratozoospermia, female partner, or single status. Clinical pregnancy rates were compared between women with AMH ≥ 1.1 and < 1.1 ng/mL. The main outcome measure was the cumulative clinical pregnancy rate after up to 4 ds-IUI cycles. RESULTS: A total of 458 ds-IUI cycles were performed among 245 patients, of whom 108 (44.08%) achieved clinical pregnancy within 4 cycles, 60.2% of these occurring in the first attempt and 84.2% after two attempts. We found no significant differences in AMH levels or other parameters (such as age, BMI, FSH, AFC) between women who became pregnant and those who did not. Cumulative pregnancy rates and logistic regression analysis revealed that AMH ≥ 1.1 ng/mL was not predictive of ds-IUI success. While a high positive correlation was observed between AFC and AMH (r = 0.67, p < 0.001), ROC curve analyses indicated that neither of these ovarian reserve markers accurately forecasts cumulative ds-IUI outcomes in non-infertile women. CONCLUSIONS: The findings of this multicenter study suggest that AMH is not a reliable predictor of pregnancy in non-infertile women undergoing ds-IUI. Even women with low AMH levels can achieve successful pregnancy outcomes, supporting the notion that diminished ovarian reserve should not restrict access to ds-IUI treatments in eligible non-infertile women.

A short versus a long time interval between semen collection and intrauterine insemination: a randomized controlled clinical trial.

STUDY QUESTION: Does a short interval (i.e. ≤90 min), compared to a long interval (i.e. ≥180 min), between semen collection and intrauterine insemination (IUI) increase the cumulative chance of an ongoing pregnancy after six IUI cycles? SUMMARY ANSWER: A long interval between semen collection and IUI resulted in a borderline significant improvement in cumulative ongoing pregnancies and a statistically significant shorter time to pregnancy. WHAT IS KNOWN ALREADY: Retrospective studies assessing the effect of the time interval between semen collection and IUI on pregnancy outcomes have shown inconclusive results. Some studies have indicated a beneficial effect of a short interval between semen collection and IUI on IUI outcomes, while others have not found any differences. To date, no prospective trials have been published on this subject. STUDY DESIGN, SIZE, DURATION: The study was performed as a non-blinded, single-center RCT with 297 couples undergoing IUI treatment in a natural or stimulated cycle. The study was conducted between February 2012 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples with unexplained or mild male subfertility and an indication for IUI were randomly assigned for up to six IUI cycles into either the control group (long interval, i.e. 180 min or more between semen collection and insemination) or the study group (short interval, i.e. insemination as soon as possible after semen processing and within 90 min of semen collection). The study was carried out in an academic hospital-based IVF center in the Netherlands. The primary endpoint of the study was ongoing pregnancy rate per couple, defined as a viable intrauterine pregnancy at 10 weeks after insemination. MAIN RESULTS AND THE ROLE OF CHANCE: In the short interval group, 142 couples were analyzed versus 138 couples in the long interval group. In the intention-to-treat (ITT) analysis, the cumulative ongoing pregnancy rate was significantly higher in the long interval group (71/138; 51.4%) compared to that in the short interval group (56/142; 39.4%; relative risks 0.77; 95% CI 0.59-0.99; P = 0.044). The time to pregnancy was significantly shorter in the long interval group (log-rank test, P = 0.012). A Cox regression analysis showed similar results (adjusted hazard ratio 1.528, 95% CI 1.074-2.174, P = 0.019). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are the non-blinded design, the long inclusion and follow-up period of nearly seven years and the large number of protocol violations, especially because they predominantly occurred in the short interval group. The non-significant results in the per-protocol (PP) analyses and the weaknesses of the study should be taken into account in the assessment of the borderline significance of the results in the ITT analyses. WIDER IMPLICATIONS OF THE FINDINGS: Because it is not necessary to perform the IUI immediately after semen processing, there can be more time available to choose the optimum work-flow and clinic occupancy. Clinics and laboratories should find their optimal timing of insemination, considering the time between human chorionic gonadotropin injection and insemination in relation to the sperm preparation techniques used as well as the storage time and conditions until insemination. STUDY FUNDING/COMPETING INTEREST(S): There were no external funding and no competing interests to declare. TRIAL REGISTRATION NUMBER: Dutch trial registry, trial registration number NTR3144. TRIAL REGISTRATION DATE: 14 November 2011. DATE OF FIRST PATIENT'S ENROLLMENT: 5 February 2012.

Update on artificial insemination: Semen, techniques, and sow fertility.

Over the years, reproductive efficiency in the swine industry has focused on reducing the sperm cell number required per sow. Recent advances have included the identification of subfertile boars, new studies in extended semen quality control, new catheters and cannulas for intrauterine artificial insemination (AI), and fixed-time AI under commercial use. Therefore, it is essential to link field demands with scientific studies. In this review, we intend to discuss the current status of porcine AI, pointing out challenges and opportunities to improve reproductive efficiency.

Luteal phase support with progesterone does not improve pregnancy rates in patients undergoing ovarian stimulation with letrozole.

RESEARCH QUESTION: Does luteal phase support with vaginal progesterone improve clinical pregnancy rates in patients undergoing ovarian stimulation with letrozole? DESIGN: This was a retrospective cohort study of patients undergoing ovarian stimulation with letrozole paired with intrauterine insemination (IUI) or timed intercourse (TIC) from January 2018 to October 2021. The primary outcome of clinical pregnancy rate (CPR) was calculated for cycles with and without luteal phase progesterone support. Univariate logistic regressions were done to evaluate predictor variables for CPR. Clinically important covariates including age, body mass index, anti-Müllerian hormone concentration, diagnosis of ovulatory dysfunction and multifollicular development were included in a multivariate analysis evaluating the relationship between luteal progesterone use and odds of clinical pregnancy. Secondary outcomes including spontaneous abortion, biochemical pregnancy and ectopic pregnancy were calculated. Live birth rates were calculated for cycles in a secondary analysis. RESULTS: A total of 492 letrozole ovarian stimulation cycles in 273 patients were included. Of these cycles, 387 (78.7%) used vaginal progesterone for luteal support and 105 (21.3%) did not. The unadjusted CPR per cycle was 11.6% (45/387) with progesterone and 13.3% (14/105) without progesterone (P = 0.645). After adjusting for significant covariates including age, BMI, diagnosis of ovulatory dysfunction and multifollicular development, the odds for clinical pregnancy were not significantly improved in cycles with exogenous progesterone (odds ratio [OR] 1.15, 95% confidence interval [CI] 0.48-2.75, P = 0.762). A follow-up analysis demonstrated that live birth rate was 10.7% (41/384) with and 12.5% (13/104) without luteal progesterone, respectively (P = 0.599). CONCLUSIONS: Luteal support with vaginal progesterone does not significantly improve CPR in ovarian stimulation cycles using letrozole.

Optimal lead follicle size in letrozole human menopausal gonadotrophin intrauterine insemination cycles with and without spontaneous LH surge.

RESEARCH QUESTION: What is the optimal lead follicle size in letrozole, human menopausal gonadotrophin and intrauterine insemination (IUI) cycles with and without spontaneous LH surges? DESIGN: This retrospective cohort study included 3797 letrozole HMG IUI cycles between January 2010 and May 2021. All cycles were divided into two groups: the HCG trigger group (trigger day LH ≤15 mIU/ml) and the spontaneous LH surge group (trigger day LH >15 mIU/ml). These two groups were subdivided into smaller groups based on the diameter of the follicles. The primary outcome measure was clinical pregnancy rate. Logistic regression analysis was conducted to explore other risk factors. RESULTS: In the HCG trigger group, the clinical pregnancy rate varied significantly, with rates of 20.8%, 14.9% and 11.8% for the 16.1-18.0, 18.1-20.0 and 20.1-22.0 mm groups, respectively (P = 0.005). In the spontaneous LH surge group, the pregnancy rate of follicles within 14.1-16.0 mm was significantly higher than that of follicles within 20.1-22.0 mm (adjusted OR 0.533, 95% CI 0.308 to 0.923, P = 0.025). Also, patients with two lead follicles were 2.569 times more likely to achieve a clinical pregnancy than those with only one lead follicle (adjusted OR 2.569, 95% CI 1.258 to 5.246, P = 0.010). The duration of infertility was also found to be a common influencing factor in both groups. CONCLUSIONS: The optimal lead follicle size was between 16.1 and 18.0 mm in HCG-triggered letrozole HMG IUI cycles. If the lead follicle size is relatively small (14.1-18.0 mm) when a spontaneous LH surge occurs, there is no need to cancel the IUI cycle.

Impact of recurrent pregnancy loss history on reproductive outcomes in women undergoing fertility treatment.

BACKGROUND: Recurrent pregnancy loss negatively affects the reproductive outcomes of natural conception. Preimplantation genetic testing for aneuploidies has been the focus of interventions in women with recurrent pregnancy loss. However, the risk of no embryos being available, high costs, and uncertainties surrounding its effectiveness limit its use. Factors beyond euploidy, such as an appropriate intrauterine environment, are also important for improving the reproductive outcomes in women with recurrent pregnancy loss. It remains unknown whether a history of recurrent pregnancy loss can affect reproductive outcomes after fertility treatment. OBJECTIVE: This study aimed to investigate the impact of history of recurrent pregnancy loss on the reproductive outcomes of women undergoing fertility treatment. STUDY DESIGN: This was a retrospective cohort study of women who underwent their first frozen embryo transfer cycle or intrauterine insemination cycle between January 2014 and July 2020 in Shanghai, China. We excluded couples with known karyotypic abnormalities (eg, balanced translocation) or uterine malformation. We performed multivariate binary logistic regressions for biochemical pregnancy, miscarriage, and live birth rates to investigate the associations between recurrent pregnancy loss history and reproductive outcomes. RESULTS: A total of 29,825 women who underwent frozen embryo transfer cycles and 5476 women who underwent intrauterine insemination cycles were included in this study. In those who underwent frozen embryo transfer, history of recurrent pregnancy loss was not significantly associated with biochemical pregnancy (adjusted odds ratio, 1.19; 95% confidence interval, 0.87-1.63), miscarriage (adjusted odds ratio, 0.99; 95% confidence interval, 0.78-1.26), or live birth rates (adjusted odds ratio, 0.91; 95% confidence interval, 0.79-1.06). Similarly, in frozen embryo transfer cycles that led to clinical pregnancy, recurrent pregnancy loss history was not significantly associated with live birth (adjusted odds ratio, 0.99; 95% confidence interval, 0.76-1.28) or miscarriage rates (adjusted odds ratio, 1.04; 95% confidence interval, 0.81-1.35). In women with intrauterine insemination, history of recurrent pregnancy loss showed no significant associations with fertility outcomes in all cycles ([adjusted odds ratio, 1.36; 95% confidence interval, 0.88-2.10] for live birth rate and [adjusted odds ratio, 1.74; 95% confidence interval, 0.75-4.01], for miscarriage rate) and in cycles that led to clinical pregnancy ([adjusted odds ratio, 0.70; 95% confidence interval, 0.31-1.63] for live birth rate and [adjusted odds ratio, 1.45; 95% confidence interval, 0.58-3.63] for miscarriage rate). CONCLUSION: In women without obvious chromosome abnormality and uterine malformation who undergo fertility treatment, recurrent pregnancy loss history was not significantly associated with miscarriage and live birth rates, suggesting that it has little or no prognostic value in predicting the reproductive outcomes of frozen embryo transfer or intrauterine insemination cycles.

Longitudinal study on sexual function and quality of life in infertile couples undergoing intrauterine insemination.

BACKGROUND: Cross-sectional studies have shown that sexual dysfunction and poor quality of life were prevalent among couples undergoing assisted reproduction at specific time points, but nothing is known about how these outcomes change over the course of their intrauterine insemination (IUI) journey. AIM: We investigated the longitudinal changes in sexual function and quality of life of infertile couples undergoing IUI. METHODS: Sixty-six infertile couples completed an anonymous questionnaire at 3 time points: after IUI counseling (T1), 1 day before IUI (T2), and 2 weeks after IUI (T3). The questionnaire consisted of demographic data, Female Sexual Function Index (FSFI) or International Index of Erectile Function-5, and Fertility Quality of Life (FertiQoL). OUTCOMES: Descriptive statistics, significance testing with the Friedman test, and post hoc analysis with the Wilcoxon signed rank test were used to compare changes in sexual function and quality of life at different time points. RESULTS: Overall, 18 (26.1%), 16 (23.2%), and 12 (17.4%) women and 29 (42.0%), 37 (53.6%), and 31 (44.9%) men were at risk for sexual dysfunction at T1, T2, and T3, respectively. There were significant differences in mean FSFI scores in arousal (3.87, 4.06, 4.10) and orgasm (4.15, 4.24, 4.39) domains at T1, T2, and T3. After post hoc analysis, only the increase in mean orgasm FSFI scores between T1 and T3 was statistically significant. Men's FertiQoL scores remained high during IUI (74.33-75.63 out of 100). Men also scored significantly higher than women on all FertiQoL domains except environment at the 3 time points. Post hoc analysis showed significant improvement in women's FertiQoL domain scores between T1 and T2: mind-body, environment, treatment, and total. Women's FertiQoL score at T2 for the treatment domain was also significantly higher than that at T3. CLINICAL IMPLICATIONS: Men should not be neglected during IUI as their erectile function got worse in the process, with half of the men being affected. Although women's quality of life showed some improvement during IUI, most of their scores were lower than men's. STRENGTHS AND LIMITATIONS: The use of psychometrically validated questionnaires and a longitudinal approach are the major strengths; a small sample size and the lack of a dyadic approach are the major limitations. CONCLUSION: During IUI, women's sexual performance and quality of life improved. The proportion of men having erectile problems was high for this age group, but men's FertiQoL scores remained good and were better than their partners' throughout IUI.

Pregnancy outcomes of intrauterine insemination without ovarian stimulation in couples affected by unilateral tubal occlusion and male infertility.

BACKGROUND: Information available to date regarding the pregnancy outcomes of intrauterine insemination (IUI) without ovarian stimulation (OS) in infertile patients with unilateral tubal occlusion remains scarce. The objectives of this study were to investigate for couples affected by unilateral tubal occlusion (diagnosed via hysterosalpingography (HSG)/transvaginal real-time three-dimensional hysterosalpingo-contrast sonography (TVS RT-3D-HyCoSy)) and male infertility: (1) whether significant differences exist in pregnancy outcomes between IUI with or without OS cycles, and (2) whether the pregnancy outcomes of IUI without OS in women with unilateral tubal occlusion were similar to those of women with bilateral patent tubes. METHODS: 258 couples affected by male infertility completed 399 IUI cycles. The cycles were divided into three groups: group A, IUI without OS in women with unilateral tubal occlusion; group B, IUI with OS in women with unilateral tubal occlusion; and group C, IUI without OS in women with bilateral patent tubes. The main outcome measures, including clinical pregnancy rate (CPR), live birth rate (LBR), and first trimester miscarriage rate, were compared between either groups A and B or groups A and C. RESULTS: Although the number of dominant follicles > 16 mm were significantly higher in group B than that in group A (group B vs. group A: 1.6 ± 0.6 vs. 1.0 ± 0.2, P < 0.001), the CPR, LBR, and first trimester miscarriage rate were comparable between these two groups. When comparing group C to group A, the duration of infertility was significantly longer in group C than that in group A (group A vs. group C: 2.3 ± 1.2 (year) vs. 2.9 ± 2.1 (year), P = 0.017). Except for the first trimester miscarriage rate, which was significantly higher in group A (42.9%, 3/7) than that in group C (7.1%, 2/28) (P = 0.044), no significant differences were observed in the CPR and LBR in these two groups. After adjusting for female age, body mass index, and the duration of infertility, similar results were obtained between groups A and C. CONCLUSIONS: In couples affected by unilateral tubal occlusion (diagnosed via HSG/TVS RT-3D-HyCoSy) and male infertility, IUI without OS might be an alternative treatment strategy. However, when compared to patients with bilateral patent tubes, the patients with unilateral tubal occlusion showed a higher first trimester miscarriage rate following IUI without OS cycles. Further studies are warranted to clarify this relationship.

The effect of gonadotrophin-releasing hormone agonist versus human chorionic gonadotrophin trigger on pregnancy and neonatal outcomes in Letrozole-HMG IUI cycles.

BACKGROUND: GnRHa and hCG are both used for oocyte maturation and ovulation triggering. However, GnRHa have a shorter half-life than hCG, which leads to luteal phase deficiency. Letrozole (LE) has been found to improve the luteal function. Thus, the choice of triggering strategy can be different in intrauterine insemination (IUI) cycles using LE and human menopausal gonadotropin (HMG). The aim of this study was to compare the pregnancy and neonatal outcomes of patients triggered with GnRHa versus hCG versus dual trigger in LE-IUI cycles. METHODS: This retrospective cohort study included 6,075 LE-HMG IUI cycles between January 2010 and May 2021 at a tertiary-care academic medical center in China. All cycles were divided into three groups according to different trigger strategies as hCG trigger group, GnRHa trigger group and dual trigger group. The primary outcome was clinical pregnancy rate. Logistic regression analysis was performed to explore other risk factors for clinical pregnancy rate. RESULTS: No significant difference was observed in clinical pregnancy rate between hCG, GnRHa and dual trigger cycles in LE-HMG IUI cycles (P = 0.964). The miscarriage rate was significantly lower in the GnRHa trigger group, and higher in the dual trigger group, compared with the hCG group (P = 0.045). Logistic analysis confirmed that triggering strategy was associated with miscarriage (aOR:0.427, 95%CI: 0.183-0.996, P = 0.049; aOR:0.298, 95%CI: 0.128-0.693, P = 0.005). No significant differences were observed regarding neonatal outcomes between the three groups. CONCLUSIONS: Our findings suggested that both GnRHa and dual trigger can be used to trigger ovulation in LE-HMG IUI cycles, but dual trigger must be used with caution.

The impact of anti-Müllerian hormone on endometrial thickness in gonadotropin stimulation/intrauterine insemination cycles: is there an effect on pregnancy outcomes?

PURPOSE: To study the association, if any, between anti-Müllerian hormone (AMH) and pre-ovulatory endometrial thickness (ET) in gonadotropin/intrauterine insemination (IUI) cycles. METHODS: This retrospective cohort study included a total of 964 patients undergoing 1926 gonadotropin/IUI cycles at an academic fertility center. Primary outcome measure was the association between serum AMH and measured ET on the day of and the day before human chorionic gonadotropin hormone (hCG) ovulation trigger. The effect of a model combining AMH and ET on early pregnancy outcomes was a secondary measure. RESULTS: In 52.8% of cycles, ET was last assessed and recorded on the day of hCG administration, while in the remaining 47.2% on the day prior to trigger. In unadjusted regression models, AMH was weakly correlated with ET on hCG trigger day [bAMH (95%CI) = 0.032 (- 0.008, 0.070), p = 0.015]. When adjusting for potential confounders, the positive correlation became significant [0.051 (0.006, 0.102), p = 0.047]. Similar findings were observed when assessing the correlation between AMH and ET on the day prior to hCG trigger. ET was non-significantly associated with the odds of clinical pregnancy, when adjusting for potential confounders, except for when restricting the analysis to couples with idiopathic infertility [OR (95%CI), p-value: 0.787 (0.623, 0.993), 0.044]. CONCLUSION: Our findings support an effect of serum AMH on endometrial development in gonadotropin induced cycles, even when adjusting for the diagnosis of PCOS. ET was not associated with the odds of achieving a clinical pregnancy, except for couples with idiopathic infertility.