Endometriosis, staging, infertility and assisted reproductive technology: time for a rethink.

How endometriosis causes infertility, with the exception of tubal dysfunction caused by adhesions, is unclear. The inflammatory milieu in the pelvis and impaired receptivity of the eutopic endometrium are considered to be possible factors. Anatomical staging systems fail to predict the fertility status of endometriosis patients. Data from assisted reproductive technology cycles consistently suggest that oocytes from patients with endometriosis have a normal potential to develop into euploid blastocysts. Moreover, oocyte or embryo recipients with endometriosis seem to have similar or slightly lower pregnancy and live birth rates compared with recipients without endometriosis, suggesting that eutopic endometrium is not or is only minimally affected, which may be caused by undiagnosed adenomyosis. In-vivo observations from women with endometriomas provide evidence against a detrimental effect of endometriomas on oocytes. Combined with the absence of an obvious improvement in fertility following the surgical destruction or excision of peritoneal endometriosis or from temporary medical suppression of the disease and the associated inflammation, the available evidence makes endometriosis-associated infertility questionable in the absence of tubal dysfunction caused by adhesions. It is likely that no anatomical staging will correlate with fertility beyond assessing tubal function. In patients with endometriosis assisted reproductive technology is as effective as for other indications.

Walking on thin endometrium.

PURPOSE OF REVIEW: Endometrial thickness has been regarded a predictor of success in assisted reproductive technology cycles and it seems a common practice to cancel embryo transfer when it is below a cut-off. However, various cut-offs have been proposed without a causal relationship between endometrial thickness and embryo implantation being established, casting doubt on the current dogma. RECENT FINDINGS: Methodological limitations of the available studies on endometrial thickness are increasingly recognized and better designed studies do not demonstrate a cut-off value which requires cancelling an embryo transfer. SUMMARY: Endometrium is important for implantation and a healthy pregnancy; however, ultrasound measured thickness does not seem to be a good marker of endometrial function.

Demographic distributions and clinical results of assisted reproduction techniques in Turkey in 2019: a descriptive survey.

Objective: The aim of this study was to describe characteristics and outcomes of assisted reproductive technology (ART) cycles performed in 2019 in Turkey. Material and Methods: One-hundred and sixty-five ART centers in Turkey were invited to submit data. The survey was sent to center directors via e-mail with anonymous links by Qualtrics™. The survey involved questions about their patient characteristics, clinical practices, and outcomes. Results: Forty-one (24.8%) centers responded to e-mails, and data gathered from 25 centers was included in the analyses. In 25 centers, 18,127 fresh or frozen transfers were carried out during the study period, of which 7796 (43.0%) were fresh and the rest were either frozen (45.2%) or embryo transfers (ET) with preimplantation genetic testing (PGT) (11.8%). The live birth rate per ET was as 30.6%, 40.1%, and 50.7% in fresh, frozen and PGT cycles, respectively. A single embryo was transferred in 65.3% of all transfers and singleton live births comprised 86.1% of all deliveries. For cycles with intrauterine insemination, 1407 were started in 2019, and 195 clinical pregnancies, 150 live births with 19 multiple pregnancies occurred. A total of 1513 ART cycles were initiated for foreign patients. Russia (29.6%), Germany (7.4%), Iraq (4.6%), Uzbekistan (3.1%), and Syria (1.4%) were the top five countries with most patients coming to Turkey for ART. Conclusion: The survey results are in parallel with the reports of international institutions and organizations. With repeated editions, the data collected with annual surveys can be used to inform ART practices in the coming years.

Does recurrent implantation failure exist? Prevalence and outcomes of five consecutive euploid blastocyst transfers in 123 987 patients.

STUDY QUESTION: What are the clinical pregnancy and live birth rates in women who underwent up to two more euploid blastocyst transfers after three failures in the absence of another known factor that affects implantation? SUMMARY ANSWER: The fourth and fifth euploid blastocyst transfers resulted in similar live birth rates of 40% and 53.3%, respectively, culminating in a cumulative live birth rate of 98.1% (95% CI = 96.5-99.6%) after five euploid blastocyst transfers. WHAT IS KNOWN ALREADY: The first three euploid blastocysts have similar implantation and live birth rates and provide a cumulative live birth rate of 92.6%. STUDY DESIGN, SIZE, DURATION: An international multi-center retrospective study was conducted at 25 individual clinics. The study period spanned between January 2012 and December 2022. A total of 123 987 patients with a total of 64 572 euploid blastocyst transfers were screened for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a history of any embryo transfer at another clinic, history of any unscreened embryo transfer at participating clinics, parental karyotype abnormalities, the use of donor oocytes or a gestational carrier, untreated intracavitary uterine pathology (e.g. polyp, leiomyoma), congenital uterine anomalies, adenomyosis, communicating hydrosalpinx, endometrial thickness <6 mm prior to initiating of progesterone, use of testicular sperm due to non-obstructive azoospermia in the male partner, transfer of an embryo with a reported intermediate chromosome copy number (i.e. mosaic), preimplantation genetic testing cycles for monogenic disorders, or structural chromosome rearrangements were excluded. Ovarian stimulation protocols and embryology laboratory procedures including trophectoderm biopsy followed the usual practice of each center. The ploidy status of blastocysts was determined with comprehensive chromosome screening. Endometrial preparation protocols followed the usual practice of participating centers and included programmed cycles, natural or modified natural cycles. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 105 (0.085% of the total population) patients met the criteria and underwent at least one additional euploid blastocyst transfer after failing to achieve a positive pregnancy test with three consecutive euploid blastocyst transfers. Outcomes of the fourth and fifth euploid blastocyst transfers were similar across participating centers. Overall, the live birth rate was similar with the fourth and fifth euploid blastocysts (40% vs 53.3%, relative risk = 1.33, 95% CI = 0.93-1.9, P value = 0.14). Sensitivity analyses excluding blastocysts biopsied on Day 7 postfertilization, women with a BMI >30 kg/m2, cycles using non-ejaculate or donor sperm, double-embryo transfer cycles, and cycles in which the day of embryo transfer was modified due to endometrial receptivity assay test result yielded similar results. Where data were available, the fourth euploid blastocyst had similar live birth rate with the first one (relative risk = 0.84, 95% CI = 0.58-1.21, P = 0.29). The cumulative live birth rate after five euploid blastocyst transfers was 98.1% (95% CI = 96.5-99.6%). LIMITATIONS, REASONS FOR CAUTION: Retrospective design has its own inherent limitations. Patients continuing with a further euploid embryo transfer and patients dropping out from treatment after three failed euploid transfers can be systematically different, perhaps with regard to ovarian reserve or economic status. WIDER IMPLICATION OF THE FINDINGS: Implantation failure seems to be mainly due to embryonic factors. Given the stable and high live birth rates up to five euploid blastocysts, unexplained recurrent implantation failure should have a prevalence of <2%. Proceeding with another embryo transfer can be the best next step once a known etiology for implantation failure is ruled out. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Association of 'normal' early follicular FSH concentrations with unexpected poor or suboptimal response when ovarian reserve markers are reassuring: a retrospective cohort study.

RESEARCH QUESTION: Are basal FSH measurements, when elevated within its normal range, useful for assessing overall ovarian response and predicting unexpected poor or suboptimal ovarian response? DESIGN: Retrospective cohort study of ovarian stimulation cycles. RESULTS: A total of 1058 ovarian stimulation cycles (891 first, 167 repeated) were included. Anti-Müllerian hormone (AMH) values were categorized into four (0 to ≤0.6, >0.6 to ≤1.2, >1.2 to ≤3.0, >3.0 to ≤6.25 ng/ml) and basal FSH levels into four groups (<25th percentile: >3.5 to 6.1 IU/ml; 25-75th percentile: >6.1 to ≤8.5 IU/ml; >75-90th percentile: >8.5 to ≤9.9 IU/ml; >90th percentile: >9.9 to ≤12.5 IU/ml). Including only first cycles, a significant independent effect of basal FSH on retrieved cumulus-oocyte complex (COC) count was seen for all basal FSH categories (>90th, >75 to ≤90th, >25 to ≤75th compared with ≤25th percentile, P < 0.001, P = 0.001 and P = 0.007, respectively), when adjusted for age, body mass index (BMI), AMH, antral follicle count (AFC), starting dose and gonadotrophin type. Including only first cycles, patients aged 35 years or older with AFC of 5 or above and AMH 1.2 ng/ml or above, showed significantly higher odds of unexpected poor or suboptimal response if they had higher basal FSH values. Most prominently in the above 90th percentile group (OR 8.64, 95% CI 2.84 to 28.47 compared with <25th percentile) but lower categories (>25th to ≤75th percentile: OR 3.04, 95% CI 1.42 t 6.99; >75th to ≤90th percentile: OR 3.47, 95% CI 1.28 to 9.83 compared with ≤25th percentile) also showed a significant association after adjusting for age, AMH, BMI, AFC, dose, and gonadotrophin type. In patients with a second cycle, an increase in FSH levels in the second round compared with the first was associated with fewer retrieved COCs (estimate: -0.44, 95% CI -0.44 to -0.05, P = 0.027). This effect was adjusted for changes in age, FSH, AFC, starting dose, stimulation duration and change in medication type. CONCLUSIONS: Basal FSH is independently associated with overall ovarian response. Moreover, it is associated with unexpected poor or suboptimal response in patients, who would fulfill POSEIDON group 2 criteria after oocyte retrieval.

Chapter 11. Endometriosis-related complications in women undergoing in-vitro fertilization.

As a chronic inflammatory disease, endometriosis generates fibrosis and anatomic distortion, which add extra-challenges to assisted reproductive technology cycles and requires a personalized approach. Patients with endometriomas have significantly decreased ovarian reserve and the ultrasound examination tends to be challenging, possibly underestimating follicle counts. It is crucial to assess the feasibility of oocyte retrieval procedure during the initial examination of the patient, as the distortion of the pelvic anatomy, the presence of hydrosalpinges and endometriomas might render the procedure difficult and increase the risk of complications. Possible injury to adjacent organs and risk of infection must be considered. Assisted reproductive technology seems to have limited or no impact on endometriosis recurrence, pain symptom progression or the size of endometrioma.

Progestin-primed ovarian stimulation: for whom, when and how?

Progestin-primed ovarian stimulation (PPOS) is being increasingly used for ovarian stimulation in assisted reproductive technology. Different progestins have been used with similar success. The available studies suggest a similar response to ovarian stimulation with gonadotrophin-releasing hormone (GnRH) analogues. Any differences in the duration of stimulation or gonadotrophin consumption are minor and clinically insignificant. PPOS has the advantage of oral administration and lower medication costs than GnRH analogues. As such it is clearly more cost-effective for fertility preservation and planned freeze-all cycles, but when fresh embryo transfer is intended PPOS can be less cost-effective depending on the local direct and indirect costs of the additional initial frozen embryo transfer cycle. Oocytes collected in PPOS cycles have similar developmental potential, including blastocyst euploidy rates. Frozen embryo transfer outcomes of PPOS and GnRH analogue cycles seem to be similar in terms of both ongoing pregnancy/live birth rates and obstetric and perinatal outcomes. While some studies have reported lower cumulative live birth rates with PPOS, they have methodological issues, including arbitrary definitions of the cumulative live birth rate. PPOS has been used in all patient types (except progesterone receptor-positive breast cancer patients) with consistent results and seems a patient friendly and cost-effective choice if a fresh embryo transfer is not intended.

Reliability of hypo-osmotic swelling test on fresh and frozen-thawed ejaculated or testicular immotile sperm: A sibling oocyte study.

The viability of sperm is a crucial factor for achieving a successful pregnancy in intracytoplasmic sperm injection (ICSI) cycles. The aim of this study was to evaluate the accuracy of the hypo-osmotic swelling test (HOST) in fresh and frozen-thawed sperm samples of different origins (ejaculated/testicular). A retrospective analysis was conducted on the outcomes of 2167 oocytes subjected to ICSI using motile and immotile-HOST-positive sperm from 2011 to 2023. We evaluated embryonic development, as well as clinical, obstetric, and neonatal outcomes in four groups based on different sperm origins (ejaculated/testicular) and processing (fresh/frozen). When comparing the results of ICSI between motile and immotile-HOST-positive sperm within each group, it was observed that there were no significant differences in the outcomes for fresh samples. However, for frozen-thawed samples, fertilization rates and blastocyst development rates were significantly lower when ICSI was performed with immotile-HOST-positive sperm compared to motile sperm. Of note, clinical, obstetric, and neonatal outcomes were statistically similar across all groups. Our findings indicate that HOST is more reliable in fresh samples than in those subjected to the freeze-thaw process. Nonetheless, HOST is considered a safe method for selecting viable sperm in all subgroups.

Should the trigger to oocyte retrieval interval be different in progestin-primed ovarian stimulation cycles?

RESEARCH QUESTION: Does the trigger to oocyte retrieval interval (TORI) affect oocyte maturation rates differently in progestin-primed ovarian stimulation (PPOS) and gonadotrophin-releasing hormone (GnRH) antagonist cycles? DESIGN: This was a retrospective cohort study. The interaction between the stimulation protocol and TORI was assessed in a linear mixed effects multivariable regression analysis with oocyte maturation rate as the dependent variable, and stimulation protocol (GnRH antagonist or PPOS), age (continuous), gonadotrophin type (FSH or human menopausal gonadotrophin), trigger (human chorionic gonadotrophin [HCG] or GnRH agonist), TORI (continuous) and days of stimulation (continuous) as the independent variables. Oocyte maturation rate was defined as number of metaphase II oocytes/number of cumulus-oocyte complexes retrieved. The maturation rate was calculated per cycle and treated as a continuous variable. RESULTS: A total of 473 GnRH antagonist and 205 PPOS cycles (121 conventional PPOS and 84 flexible PPOS) were analysed. The median (quartiles) female age was 36 (32-40) years. Of these cycles, 493 were triggered with HCG and 185 with a GnRH agonist. The TORI ranged between 33.6 and 39.1 h, with a median (quartiles) of 36.2 (36-36.4) hours. Maturation rates were similar between fixed PPOS, flexible PPOS and antagonist cycles (median 80%, 75% and 75%, respectively, P = 0.15). There was no significant interaction between the stimulation protocols and TORI for oocyte maturation. CONCLUSIONS: PPOS cycles do not seem to require a longer TORI than GnRH antagonist cycles.

Free your patients and yourself from day 2-3: start ovarian stimulation any time in freeze-all cycles.

Ovarian stimulation for assisted reproductive technology is traditionally started in the early follicular phase. The essential rationale is to allow timely follicle growth and oocyte retrieval to ensure synchronization of the in-vitro cultured embryos with the receptive period of the endometrium in a fresh transfer cycle. In addition, conventional thought suggested that follicle recruitment happened only once, around menstruation. A deeper understanding of folliculogenesis, advances in cryobiology and an increasing proportion of freeze-all cycles provide a unique opportunity here. Experience from oncofertility patients as well as infertile women and oocyte donors who underwent ovarian stimulation in different phases of the menstrual cycle, dubbed 'random start' cycles, suggests that the number of oocytes collected and their reproductive potential do not depend on the time of starting ovarian stimulation, although the duration of stimulation and gonadotrophin consumption can vary slightly. It may be time to free both patients and clinics from the obsession with starting ovarian stimulation in the early follicular phase in planned freeze-all cycles. The flexibility provided by random start cycles is one aspect of individualizing treatment to patients' needs.

A critical appraisal of studies on endometrial thickness and embryo transfer outcome.

A receptive endometrium is required for successful embryo implantation. Endometrial thickness, as measured by ultrasonography, is the most commonly used marker of endometrial receptivity in assisted reproductive technology cycles. Several factors simultaneously affect both endometrial thickness and probability of live birth, including age, oestradiol concentration and oocyte number, among others. Most of the studies investigating a relationship between endometrial thickness and embryo transfer outcomes are retrospective and do not adequately address confounding factors, in addition to other limitations. Despite multiple meta-analyses and studies with large numbers of cycles, controversy still exists. The difference between the results from prospective and retrospective studies is also striking. This article presents a critical appraisal of the studies on endometrial thickness and embryo transfer outcomes in order to highlight methodological issues and how they can be overcome in future studies. Currently available evidence does not seem to support a modification of management just because endometrial thickness is below an arbitrary threshold.

Interindividual variation of progesterone elevation post LH rise: implications for natural cycle frozen embryo transfers in the individualized medicine era.

BACKGROUND: The key to optimal timing of frozen embryo transfer (FET ) is to synchronize the embryo with the receptive phase of the endometrium. Secretory transformation of the endometrium is induced by progesterone. In contrast, detection of the luteinizing hormone (LH) surge is the most common surrogate used to determine the start of secretory transformation and to schedule FET in a natural cycle. The accuracy of LH monitoring to schedule FET in a natural cycle relies heavily on the assumption that the period between the LH surge and ovulation is acceptably constant. This study will determine the period between LH rise and progesterone rise in ovulatory natural menstrual cycles. METHODS: Retrospective observational study including 102 women who underwent ultrasound and endocrine monitoring for a frozen embryo transfer in a natural cycle. All women had serum LH, estradiol and progesterone levels measured on three consecutive days until (including) the day of ovulation defined with serum progesterone level exceeding 1ng/ml. RESULTS: Twenty-one (20.6%) women had the LH rise 2 days prior to progesterone rise, 71 (69.6%) had on the day immediately preceding progesterone rise and 10 (9.8%) on the same day of progesterone rise. Women who had LH rise 2 days prior to progesterone rise had significantly higher body mass index and significantly lower serum AMH levels than women who had LH rise on the same day with progesterone rise. CONCLUSION: This study provides an unbiased account of the temporal relationship between LH and progesterone increase in a natural menstrual cycle. Variation in the period between LH rise and progesterone rise in ovulatory cycles likely has implications for the choice of marker for the start of secretory transformation in frozen embryo transfer cycles. The study participants are representative of the relevant population of women undergoing frozen embryo transfer in a natural cycle.

Effect of the endometrial thickness on the live birth rate: insights from 959 single euploid frozen embryo transfers without a cutoff for thickness.

OBJECTIVE: To investigate whether endometrial thickness (ET) independently affects the live birth rate (LBR) after embryo transfer. DESIGN: Retrospective study. SETTING: Private assisted reproductive technology center. PATIENT(S): A total of 959 single euploid frozen embryo transfers. INTERVENTION(S): Vitrified euploid blastocyst transfer. MAIN OUTCOME MEASURE(S): Live birth rate per embryo transfer. RESULT(S): The conditional density plots did not demonstrate either a linear relationship between the ET and LBR or a threshold below which the LBR decreased perceivably. Receiver operating characteristic curve analyses did not suggest a predictive value of the ET for the LBR. The area under the curve values were 0.55, 0.54, and 0.54 in the overall, programmed, and natural cycle transfers, respectively. Logistic regression analyses with age, embryo quality, day of trophectoderm biopsy, body mass index, and ET did not suggest an independent effect of the ET on the LBR. CONCLUSION(S): We did not identify a threshold of the ET that either precluded live birth or under which the LBR decreases perceivably. Common practice of cancelling embryo transfers when the ET is <7 mm may not be justified. Prospective studies, in which the management of the transfer cycle would not be altered by ET, would provide higher-quality evidence on the subject.

Why ovarian stimulation should be aimed to maximize oocyte yield.

The ultimate measure of success of assisted reproductive technology (ART) is the cumulative live birth rate (CLBR) per ovarian stimulation cycle, which increases with every oocyte collected. However, the adverse effects of ovarian stimulation on endometrial receptivity, as well as the risks of ovarian hyperstimulation syndrome (OHSS) and adverse obstetric and neonatal outcomes, are observed to increase with ovarian response to stimulation. To mitigate these risks, mild stimulation has been hailed as the safer patient-friendly approach with the additional benefit of cutting the cost of gonadotrophins. Yet accumulating data demonstrate the absence of an adverse effect of ovarian stimulation on oocytes as well as on obstetric and neonatal outcomes, and multiple preventive strategies have been introduced for OHSS. The widespread use of vitrification revolutionized ART by enabling the liberal use of cycle segmentation to minimize the risk of OHSS and avoid impaired endometrial receptivity due to ovarian stimulation. Vitrification also allowed every oocyte to contribute to the CLBR. Thus, it is questionable whether the cost savings from gonadotrophins during the index ovarian stimulation offset the cost saving by preventing repeat ovarian stimulation and repeat laboratory procedures per live birth. This paper aims to prove by contradiction that ovarian stimulation should be aimed to maximize oocyte yield.

Recurrent implantation failure: reality or a statistical mirage?: Consensus statement from the July 1, 2022 Lugano Workshop on recurrent implantation failure.

IMPORTANCE: To date, recurrent implantation failure (RIF) has no clear definition and no clearly identified impaired function. Hence, the term RIF is currently used somewhat haphazardly, on the basis of clinicians' judgment. OBJECTIVE: International experts in reproductive medicine met on July 1, 2022, in Lugano, Switzerland, to review the different facets of RIF and define the diagnosis and its appropriate management. EVIDENCE REVIEW: A systematic review without meta-analysis of studies published in English from January 2015 to May 2022. FINDINGS: Data indicated that RIF has been largely overevaluated, overdiagnosed, and overtreated without sufficient critical assessment of its true nature. Our analyses show that true RIF is extremely uncommon-occurring in <5% of couples with infertility-and that reassurance and continued conventional therapies are warranted in most cases of assisted reproductive technology (ART) failure. Although the true biologic determinants of RIF may exist in a small subset of people with infertility, they elude the currently available tools for assessment. Without identification of the true underlying etiology(ies), it is reasonable not to assign this diagnosis to a patient until she has failed at least 3 euploid blastocyst transfers (or the equivalent number of unscreened embryo transfers, adjusted to the patient's age and corresponding euploidy rate). In addition, other factors should be ruled out that may contribute to her reduced odds of sustained implantation. In such cases, implantation failure should not be the only issue considered in case of ART failure because this may result from multiple other factors that are not necessarily repetitive or persistent. In reality, RIF impacting the probability of further ART success is a very rare occurrence. CONCLUSION: True RIF is extremely uncommon, occurring in <5% of couples with infertility. Reassurance and continued conventional therapies are warranted in most cases. It would seem reasonable not to assign this diagnosis to a patient until she has failed at least 3 euploid embryo transfers (or the equivalent number of unscreened embryos, adjusted to her age). RELEVANCE: Given the number of internationally recognized experts in the field present at the Lugano meeting 2022, our publication constitutes a consensus statement.