Treatment options for endometrial hypoproliferation.

PURPOSE OF REVIEW: Endometrial hypoproliferation refers to the failure of the endometrium to reach optimal thickness during fresh or frozen embryo transfer cycles in women undergoing infertility treatment with in-vitro fertilization (IVF). This review discusses the treatment options for endometrial hypoproliferation. RECENT FINDINGS: Apart from factors related to the embryo quality, ultrasonographic findings associated with the endometrium, such as endometrial thickness, endometrial pattern and subendometrial blood flow, are considered key factors associated with the outcome of assisted reproductive treatment. To date, a consensus has not been reached regarding the definition of thin endometrium, while thresholds of 6, 7 or 8 mm have been used in the literature. Strategies to increase endometrial thickness can be reviewed in three groups: endocrine approaches, vitamins & supplements, and new experimental therapeutic interventions. Some of the recently introduced experimental therapeutic interventions such as platelet-rich plasma injection, stem cell treatment and tissue bioengineering are exciting potential therapies that need to be further studied. SUMMARY: Despite a large number of publications on the topic, diagnosing and treating endometrial hypoproliferation remains a challenge. Well designed studies are needed to establish a widely accepted endometrial thickness cut-off value below which endometrial hypoproliferation is diagnosed and to generate meaningful data that would allow an evidence-based discussion of available therapeutic options with patients.

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.

Probability of Pregnancy With Mono vs Multiple Folliculogenesis in Women With Unexplained Infertility.

Context: Ovarian stimulation (OS) increases pregnancy rates but can cause multiple folliculogenesis and multiple pregnancy. Objective: To determine whether the probability of pregnancy differs in OS cycles with mono- vs multifolliculogenesis in women with unexplained infertility (UI). Design: Secondary analysis of a multicenter, randomized controlled trial: Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation with 3 treatment arms: gonadotropins, clomiphene, or letrozole, combined with intrauterine insemination. Women were categorized as having either 1 or ≥ 2 mature follicles (≥ 16 mm). Relative risk (RR) and 95% CIs for clinical pregnancy and live birth by number of follicles were estimated using generalized linear models adjusted for age, body mass index, years of infertility, and history of prior live birth. Setting: 12 US-based clinical sites. Participants: Normally cycling women aged 18 to 40 years with a normal uterine cavity and at least 1 patent fallopian tube. Male partners with ≥ 5 million total motile sperm. Interventions: Gonadotropins, clomiphene, or letrozole with insemination. Main Outcome Measures: Clinical pregnancy rates (CPR) and live birth rates (LBR). Results: A single mature follicle > 16 mm resulted in lower CPR (RR, 0.70; 95% CI, 0.54-0.90) and LBR (RR, 0.67; 95% CI, 0.51-0.89) compared with ≥ 2 mature follicles. When stratified by treatment modality, no association of follicle number with CPR or LBR was observed for letrozole or clomiphene, but women using gonadotropins had lower CPR and LBR with monofolliculogenesis. Conclusion: In couples undergoing gonadotropin treatment for UI, monofolliculogenesis following OS is related to a lower rate of live birth.

Gonadotropin receptor polymorphisms (FSHR N680S and LHCGR N312S) are not predictive of clinical outcome and live birth in assisted reproductive technology.

OBJECTIVE: To study the consequences of specific genotype profiles of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone choriogonadotropin receptor (LHCGR) on assisted reproductive technology outcomes when preimplantation genetic testing for aneuploidy is used for controlling the embryo ploidy status. The most common reported single-nucleotide polymorphisms in the amino acid position for the FSHR (N680S; N: asparagine, S: serine; [rs6166]) and the LHCGR (N312S variant; N: asparagine, S: serine [rs2293275]) were chosen for this study. DESIGN: Retrospective cohort study. SETTING: Private Fertility Clinic. PATIENT(S): All women aged 18-40 years undergoing their first assisted reproductive technology cycle with aneuploidy screening between 2006 and 2017 with body mass index of >18 and <40 kg/m2 were included. INTERVENTION(S): All patients received both recombinant follicle-stimulating hormone and human menopausal gonadotropin or low dose human chorionic gonadotropin. Genomic DNA was isolated from patients' blood. Genotyping of the FSHR and LHCGR polymorphisms was performed using TaqMan genotyping assays. Associations between both receptor genotypes and clinical outcomes were assessed using generalized regression and ANOVA. MAIN OUTCOMES MEASURE(S): Live birth rate was the primary outcome. Secondary outcomes included oocyte yield, mature oocytes, blastulation rate, usable blastocyst rate, and implantation rate. RESULT(S): A total of 1,183 patients met the inclusion criteria and generated reliable genotype results. The overall genotype frequencies in the study population for the FSHR gene were as follows: 21.7% homozygous for S in codon 680, 29.2% homozygous for N680, and 48.1% heterozygous (N680S). As for the LHCGR, 15.6% were homozygous for N312, 38.5% homozygous for S312 and 45.9% heterozygous (N312S). Our study population consisted of 53.8% non-Hispanic white; 6.1% Hispanic white; 4.1% Afro-American; 15.4% Asian; and 20.6% other or unknown. No significant association was found with any of the studied variables (oocyte yield, usable blastocyst rate, implantation rate, live birth) when genotypes were analyzed per receptor or in combination with one another. There was a statistically significant but clinically irrelevant difference in the rate of mature oocytes across different variant combinations. CONCLUSION(S): Our findings suggest that the presence of gonadotropin receptor polymorphisms in both FSHR N680S and LHCGR N312S are not associated with assisted reproductive technology outcomes; therefore, these variants should not be considered reproductive predictors.

A review of the pathophysiology of recurrent implantation failure.

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition-something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

Immunologic causes and thrombophilia in recurrent pregnancy loss.

Certain miscarriages result from immunologic factors, but there is no clear identification of the precise causes of recurrent pregnancy loss (RPL). Miscarriages and RPL can arise from a disruption of maternal-fetal immune homeostasis. Remodeling of the maternal uterine spiral arteries is one of the key steps for normal growth and development of the fetus. An adequate oxygen supply is necessary for correct placentation, and it is accomplished by proper vascular changes. The development of fetal tissues creates a potential immunologic problem since the fetus can express paternal antigens and, in some cases, antigens of a gamete donor. The maternal immune system actively responds to fetal antigens, and dysregulation of this crosstalk could partly explain pregnancy complications such as miscarriages and RPL. RPL resulting from thrombophilia is primarily due to acquired thrombophilia, and therefore screening and treatment should be focused on antiphospholipid antibody syndrome.

Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.

OBJECTIVE: To study the true prevalence of recurrent implantation failure. DESIGN: Retrospective cohort study. SETTING: A private assisted reproductive technology center. PATIENT(S): Women (n = 4,429) with anatomically normal uterus who underwent up to three consecutive frozen euploid single embryo transfers (FE-SETs) were included in the study. Cycles with donor eggs or gestational carriers were excluded. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative outcomes from these cycles were analyzed. A logistic regression model was used to assess the differences of outcomes between first, second, and third FE-SET and a Kaplan-Meier curve as used to analyze cumulative implantation rate. RESULT(S): The mean age of the patients included in the study was of 35.4 years. The sustained implantation rates of the first, second, and third FE-SET were 69.9%, 59.8%, and 60.3% per transfer, respectively. The cumulative sustained implantation rate after up to three consecutive FE-SET was 95.2%. The live birth rates after the first, second, and third FE-SET were 64.8%, 54.4%, and 54.1% per transfer, respectively. The cumulative live birth rate after up to three consecutive FE-SET was 92.6%. The miscarriage rate after observing a positive heartbeat was not different between the first (7.2%), second (8.8%), and third (12.7%) FE-SET. CONCLUSION(S): Our findings suggest that true recurrent implantation failure is rare. For those patients with the ability to make euploid blastocysts, <5% would fail to achieve a clinical pregnancy with three embryos transferred. It remains to be further investigated whether this threshold identifies a truly recalcitrant group or simply a statistical certainty based on random variation.

Male Infertility and the Future of In Vitro Fertilization.

The male contribution to infertility has traditionally been overlooked, or at best oversimplified. In recent years efforts have been made to optimize diagnostic and therapeutic techniques to maximize fertility outcomes. A renewed focus on the male partner has resulted in an increased understanding of both genetic and epigenetic changes within the male germline. Furthermore, single-nucleotide polymorphisms, copy-number variants, DNA damage, sperm cryopreservation, obesity, and paternal age have recently been recognized as important factors that play a role in male fertility. Developing a deeper knowledge of these issues could potentially lead to improved success with assisted reproductive technology.