Understanding sperm motility regulation: it’s a long road ahead Sperm motility is one of the most important markers of semen quality because it is essential for sperm to move properly through the female reproductive tract to reach and fertilize the egg. Despite decades of research, the mechanisms by which sperm acquire motility during their transit through the epididymis are not completely understood. A growing body of evidence suggests, however, that the morphological integrity of the sperm flagellum, the ability to produce energy to fuel flagellar movements, and the activation or inhibition of specific signaling pathways and protein posttranslational modifications represent key prerequisites for sperm to acquire motility.
Specificity of the lactate dehydrogenase isoenzyme index as a preoperative screen for uterine sarcoma before myomectomy To evaluate the applicability of the Uterine mass Magna Graecia (UMG) risk index (elevation defined by a lactate dehydrogenase isoenzyme index >29) in women undergoing surgery for benign fibroids and to determine whether other factors were associated with an elevated index. An elevated UMG index has been reported to be associated with an increased risk of uterine sarcoma in Italian women.
Thyroid autoantibodies: to treat or not to treat? Hypothyroidism affects approximately 2% to 4% of reproductive-age women, and subclinical hypothyroidism is even more common (1). Thyroid autoimmunity is the primary etiology of hypothyroidism. A serum antibody test is often used to diagnose its presence. Undiagnosed and uncorrected, overt hypothyroidism may lead to irregular menses with anovulatory cycles and increased risk of miscarriage, pre-eclampsia, intrauterine growth restriction, and fetal death (2). Women with overt hypothyroidism should be treated with thyroid replacement as soon as diagnosis is established to improve both their fertility and their pregnancy outcomes.
Society for Assisted Reproductive Technology advertising guidelines: how are member clinics doing? To examine whether Society for Assisted Reproductive Technology (SART) member in vitro fertilization (IVF) centers adhere to the Society’s new advertising policy, updated in January 2018, and evaluate other services advertised by region, insurance mandate and university affiliation status. Historically, a large percentage of IVF clinics have not adhered to SART guidelines for IVF clinic website advertising and have had variability in how financial incentives and other noncore fertility services are advertised.
Reunification of the unicornuate uterus and the remnant horn– proceed with caution! The unicornuate uterus is caused by the arrested development of one of the müllerian ducts and occurs in 0.1% women. Unicornuate uterus may be associated with the presence of a rudimentary horn connected to the main uterine body or with no rudimentary horn with the presence of both broad ligaments, two ovaries, and one or two fallopian tubes.
Euploidy prediction: possible or impossible? Closer or further away? It has been almost 10 years since the first papers of massive embryo analysis from new time-lapse monitoring (TLM) systems were published. After those studies, we started getting familiar with new words as “morphokinetics,” “morphology dynamics,” and “algorithms” for embryo selection (1). Since then, a significant number of scientific publications have explored the potentiality that the information provided from TLM may have on reproductive outcome expectations, a journey from blastulation prediction throughout implantation potential to euploidy forecast.
Choice of treatment to manage early miscarriage does not affect future fertility The study by Tzur et al. (1) compared short-term fertility outcomes of surgically versus medically treated women with early miscarriage. The study population included 203 women diagnosed with early pregnancy loss. The treatment protocol was chosen based on patient preference: 106 women were treated with curettage and 97 with a medical protocol including 800 μg misoprostol. Short-term pregnancy rates and outcomes did not differ between the study groups. Pregnancy rates within 6 months median time to pregnancy, as well as pregnancy rates within 12 months and proportion of pregnancies ending in live birth, did not differ between surgically and medically managed patients.
Elusive effect of endometrial thickness: through thick and thin Ovulation stimulation with intrauterine insemination is often an initial treatment option for couples with subfertility. Factors such as age and semen parameters have an established effect on the success of ovulation stimulation with intrauterine insemination; however, the impact of endometrial thickness has yet to be elucidated. Agents commonly used for ovarian stimulation include clomiphene citrate, letrozole, and gonadotropins. In some studies, clomiphene citrate has been associated with decreased endometrial thickness in ovulation stimulation with intrauterine insemination cycles.
Too much of a good thing? Total gonadotropin dose and in vitro fertilization outcomes In this issue of Fertility and Sterility, Gerber et al. conducted a retrospective cohort study using the Society for Assisted Reproductive Technology (SART) database to investigate whether the length of IVF cycle and/or total gonadotropin dose is associated with live birth rates in fresh and frozen-thawed embryo transfer (FET) cycles (1). Only first single-embryo transfer cycles without preimplantation genetic testing were included. Increased cycle length and higher total gonadotropin dose were associated with lower live birth rates in fresh and frozen cycles in a univariate analysis, but this trend was not observed in a multivariate analysis.
Fertility preservation for women with borderline ovarian tumors: fertility-sparing surgery One of the most important quality-of-life issues in young cancer patients is fertility. Currently, there are several established fertility preservation strategies available for cancer patients as a result of advances in reproductive sciences and technologies. However, options for fertility preservation for women with invasive ovarian cancer are very limited as this cancer requires radical treatment without delay. Certain procedures such as oocyte retrieval are even contraindicated because of the high risk of cancer cell spillage.
Fertility clinic advertising in the United States: is the Society for Assisted Reproductive Technology oversight of advertising policy effective? The Society for Assisted Reproductive Technology (SART) is a nonprofit organization that was founded in 1985 with an initial goal of establishing a national registry of in vitro fertilization (IVF) procedures and outcomes. The purpose of the registry was to determine clinical effectiveness, safety, and quality of care. The Society for Assisted Reproductive Technology subsequently developed the SART Clinical Outcome Reporting System, perhaps the first such registry in the United States. In vitro fertilization clinic specific outcome data voluntarily were submitted to SART, combined into a national report, and published annually since 1988 (1).
Mountains out of molehills—are we putting too much weight on morphokinetics? In this issue of Fertility and Sterility, Dr. Desai and colleagues (1) present a prospective randomized study of sibling embryos randomized between two media and cultured in the EmbryoScope (Vitrolife, Sweden) time-lapse incubator. The authors randomized 10,768 sibling 2 pronuclear embryos between the two media and compared implantation, pregnancy, and live birth rates after single embryo transfer in each group. Additionally, they compared morphokinetic parameters, development of good quality blastocysts, and euploidy rates between the groups.
New developments and controversies in uterus transplantation We have read, with great interest, “Report of the first livebirth after uterus transplantation in China” by Huang and colleagues (1), and congratulate the authors on their achievements.
Klotho: spinning up some new hype for decreased ovarian reserve research? What is the next best thing to immortality? Readers of Fertility & Sterility might answer “everlasting fertility.” Decreased ovarian reserve (DOR) and primary ovarian insufficiency (POI) have long thwarted physicians and devastated affected women. In fact, these are most difficult diagnoses to treat from both a clinical and emotional perspective. In this issue, Xu et al. (1) attempt to shed some new light on DOR by introducing Klotho, an anti-aging gene that also is gaining traction in the reproductive arena.
Nonobstructive azoospermia: a spectrum, not a single disease In the article by Majzoub et al. (1), the authors set out to create a predictive model for successful testicular sperm aspiration (TESA) in men with nonobstructive azoospermia (NOA). The authors used retrospective data from 297 men diagnosed with NOA who underwent TESA followed by microdissection testicular sperm extraction (mTESE) if sperm was not identified on TESA. Overall TESA, was successful in finding sperm in 23.6% of men, which is similar to a meta-analysis comparing TESA to mTESE (TESA was successful in 28% of NOA men) (2).
Rubik’s cube of depression, antidepressants, and fertility Women experience mood and anxiety disorders at an increased prevalence during their reproductive years. As a result, antidepressants are one of the most used prescription medication classes in the United States, used by approximately 15% of reproductive-age women between 15 and 44 years (1). In women who are actively trying to conceive, approximately 10% report antidepressant use (2). The pervasiveness of depressive disorders and subsequent antidepressant use among reproductive-age women has brought attention to concerns regarding the potential effect of these drugs on fertility.
Effects of endometriosis on assisted reproductive technology: gone with the wind Endometriosis is encountered in approximately 40% of infertile women. The mechanisms by which endometriosis causes infertility are multiple with none truly prevailing in the clinical cases commonly encountered. In addition, infertility caused by endometriosis is not absolute, but relative, as severe cases of endometriosis have even been reported in women who had conceived spontaneously. In one review article (1), we sorted all endometriosis-related factors of infertility according to the location where these are expressed, as follows: the pelvic cavity, the ovaries, and the uterus itself.
Premature progesterone rise as a trigger of polycystic ovarian syndrome Originally described as Stein-Leventhal syndrome, polycystic ovarian syndrome (PCOS) is a very common condition in women of reproductive age, characterized by hyperandrogenism, insulin resistance, the presence of multiple ovarian cysts, and irregular menstrual cycles with accompanying infertility. There is currently a consensus that genetic and epigenetic factors as well as intrauterine environment create a predisposition to PCOS (1). However, there is no agreement on whether the ovarian cysts are the cause or the result of the hyperandrogenism and insulin resistance or even whether the cysts should be used as a part of diagnostic criteria (1).
Limitations of randomization for the study of nutrition, lifestyle, and in vitro fertilization success In this issue, Oostingh and colleagues (1) report the results of a multicenter single-blinded, randomized trial performed in the Netherlands that showed modest improvements in nutritional and lifestyle behaviors in couples undergoing in vitro fertilization (IVF) after an mHealth intervention. The participants answered online questionnaires about their behaviors, resulting in access to a personalized page and text messages with tips and feedback on their inadequate behaviors. The control group only answered the online questionnaires.
It’s time to include couple-based body mass index counseling in the infertility clinic visit The impact of female abnormalities of body mass index (BMI) and its association with subfertility and increased time to pregnancy (TTP) have been well-characterized (1). This may be due to the impact of BMI on ovulatory status in women, though TTP is increased even among women with a high BMI and reportedly regular cycles (2). Patients with higher BMIs, those in the overweight and obese categories, are at increased risk for gestational issues including gestational diabetes, hypertension, and difficulty with fetal monitoring.
Why are multiple pregnancy rates and single embryo transfer rates so different globally, and what do we do about it? In the early years of in vitro fertilization, overall pregnancy rates were low, and it was considered necessary to transfer more than one embryo to increase the chances of pregnancy. It was not until advances in assisted reproductive technologies resulting in increased pregnancy rates that the concept of transferring just one embryo was considered possible. A consequence of improvements in implantation rates was also an increase in multiple pregnancies when more than one embryo was transferred. Although some countries have reduced the number of embryos transferred, international data show that in many parts of the world high twin and higher order multiple pregnancy rates still exist.
In the article by Dviri, et al. “Is there a correlation between paternal age and aneuploidy rate? An analysis of 3,118 embryos derived from young egg donors” (Fertil Steril 2020;114:293-300), the authors’ affiliations were listed incorrectly. The correct affiliations are as follows.
Advanced diagnosis of polycystic ovary syndrome—new prediction models with standard parameters Polycystic ovary syndrome (PCOS) is an endocrine condition that has been well known for decades, with a prevalence of 8% to 13% in women of reproductive age (1). It is characterized by clinical or hormone findings of androgen excess, ovulatory disorders, and infertility, and a typical ovarian appearance. Metabolic disorders such as insulin resistance can be found in the majority of PCOS patients. However, a correct diagnosis is challenging, particularly in patients who have minor clinical symptoms.
Is there a link between focal adenomyosis and infertility? The last 15 years has seen an exponential rise in the number of publications on adenomyosis, a disease first described in the 19th century (1). In 2005, 53 papers were published; over the past several years around 200 publications have appeared on PubMed. This renewed interest can be attributed not only to increased awareness but also to significantly improved technology. The quality of the ultrasound scanners we use today in clinical examination can identify a disease that previously had required the patient to undergo magnetic resonance imaging (MRI).
Growing evidence links male infertility and genitourinary malignancies Significant evidence links poor overall health with male infertility: Strong associations link infertility with obesity, cardiovascular disease, hypertension, autoimmune diseases, as well as premature mortality (1). In their systematic review and meta-analysis published in this issue of Fertility and Sterility, del Giudice et al. review the existing literature assessing the association between male-factor infertility and the risk of later developing male-specific genitourinary malignancies. Their study demonstrates that male infertility conveys a significant risk for developing both testicular cancer (risk ratio [RR] 2.03, 95% confidence interval [CI] 1.66–2.48) and prostate cancer (RR 1.68, 95% CI 1.17-2.40) (2).
Endometriosis does not impact live-birth rates in frozen embryo transfers of euploid blastocysts To determine whether subfertility in patients with endometriosis is due to impaired endometrial receptivity by comparing pregnancy and live-birth outcomes in women with endometriosis versus two control groups without suspected endometrial factors: noninfertile patients who underwent assisted reproduction to test embryos for a single-gene disorder and couples with isolated male factor infertility.
Chemotherapy and decline of the ovarian reserve: How can we explain it and how to prevent it? Understanding how chemotherapy affects gonadal function also allows us to understand the mechanisms protecting the pool of primordial follicles (namely, the ovarian reserve), and provides valuable insights into gonadoprotective agents that can be used to counter the adverse effects of toxic drugs. The effects of chemotherapeutic drugs on female reproduction began to be reported in the 1970s. The first accounts associated one particular alkylating agent, cyclophosphamide (CPM), with amenorrhea, premature ovarian insufficiency (POI), and ovarian dysfunction.
Placental pathology: crucial link in the subfertility-pregnancy outcome chain For more than 30 years, distinguishing between the effects of subfertility versus assisted reproductive technology (ART) on pregnancy outcomes has challenged the field of reproductive medicine. In the early years of in vitro fertilization, many of the increased adverse pregnancy outcomes in ART-treated women could be attributed to the higher rate of multiple gestations. However, studies assessing ART-conceived singleton pregnancies also revealed adverse outcomes, including significantly higher rates of preterm birth compared with those conceived naturally (1).
Do magnetic fields affect reproductive outcomes? Evidence against a link Magnetic fields receive substantial attention in reproductive medicine (1). Magnetic fields are ubiquitous in the environment at low levels. However, individuals in close proximity to electromagnetic field sources may be exposed to higher amounts (2, 3). Electromagnetic fields are formed by extremely-low-frequency power sources such as electrical grids and home appliances, as well as radiofrequency telecommunication devices (2, 3). Because of the constantly increasing use of electronic devices, a growing number of researchers question whether magnetic fields may be a risk factor for adverse reproductive outcomes (1, 2).
HMGA2 involvement in uterine leiomyomas development through angiogenesis activation Uterine leiomyoma (UL) is the most common benign estrogen-dependent tumor in women of reproductive age, affecting 25% of women and has a cumulative incidence of 70% in women by the age of 50 years because leiomyomas can be present without symptoms in most of them (1). However, 15% to 30% of women with UL present symptoms such as metrorrhagia, pelvic pain or pressure, and urinary incontinence, as well as infertility, miscarriage, and preterm birth. Leiomyomas arise from overgrowth of extracellular matrix and smooth muscle derived from myometrium, which contribute to tumor expansion (1).
Ectopic pregnancy: why do embryos get lost along the way? Serious morbidity and mortality, thankfully, remain rare with the use of assisted reproductive technologies (1). However, when complications do arise following fertility treatments, ectopic pregnancy is rivaled perhaps only by ovarian hyperstimulation in terms of provoking anxiety in both patient and provider alike. The potential for severity is great. Rupture, if not found in a timely fashion, can have grave consequences, potentially necessitating emergency laparotomy or even resulting in death.
Midgestation origins of androgenic and estrogenic pathophysiology in three major women’s health disorders David Barker first associated low birth weight with subsequent cardiovascular disease more than 30 years ago, framing mechanistic understanding of suboptimal gestational environments as major contributors to developmental origins of adult disease. Rapid-onset maternal immunologic tolerance of the semiallogeneic fetus is essential for optimal endothelial cell reprogramming within uterine spiral arteries, enabling optimal placental function. Not surprisingly, therefore, suboptimal gestational environments arise when preexisting maternal immunologic (inflammatory), metabolic, and endocrine disorders impair placental development and function.
New insights for fertility preservation by ovarian tissue cryopreservation and transplantation in pediatric cancer patients Premature gonadal failure is a long-term health issue in young cancer patients. For these patients, ovarian tissue cryopreservation and transplantation is currently their only available option to preserve fertility. The first successful ovarian tissue transplantation resulting in a live birth occurred in 2004; significant progress has been made to increase the efficacy of this as-yet-considered experimental procedure, resulting in >130 live births globally. Nevertheless, investigations to further improve and standardize cryopreservation and transplantation technologies continue worldwide.
Avoiding exceptionalism in reproductive endocrinology and infertility fellowship training In 2017, responsibility for subspecialty certification in obstetrics and gynecology transitioned from the American Board of Obstetrics and Gynecology to the Accreditation Council for Graduate Medicine Education (ACGME), a private not-for-profit organization that sets standards for graduate medical education in the United States in 180 specialties and subspecialties and reviews training programs for compliance with these standards. As part of this transition, leaders in the field have been working with the ACGME to develop expectations for reproductive endocrinology and infertility (REI) fellowship training programs, delineating the essential procedures that are necessary for training, and enumerating the number of each procedure that should be performed by a fellow before graduation.
Preoperative human chorionic gonadotropin in men with Klinefelter syndrome undergoing microdissection testicular sperm extraction has prognostic value, but no therapeutic benefit Klinefelter syndrome (KS) is the most common genetic abnormality present in infertile men, and the vast majority of nonmosaic KS patients will have nonobstructive azoospermia (NOA). Microdissection testicular sperm extraction (mTESE) is one of the most effective methods of obtaining testicular sperm, with approximately 50% of men with KS having sperm found at mTESE. Interventions that can optimize sperm retrieval rates (SRR), or at least more accurately guide preoperative counseling, would be of great value to the treatment of men with KS and NOA.
Intelligent light and florescence-guided surgery augmenting the surgeon’s visual perception One key issue that surgeons and scientists are looking to resolve is visibility beyond the surface. Another is a way to distinguish critical structures from each other. Doctors can only see so much inside the body under regular “white light,” but some are optimistic that sensory improvements can help them detect in real time what cannot be seen with the naked eye. Florescence-guided surgery is one step toward visual enhancement in surgery. A popular fluorophore today is indocyanine green (ICG), which has been used in several medical specialties.
New approaches in bloom: four-petal adenomyomectomy technique Adenomyosis is defined as ectopic endometrial glands within the myometrial layers of the uterus. Two main theories regarding the natural history of adenomyosis predominate: invagination of the endometrial basilis into the endometrial-myometrial interface secondary to repeated injury and repair, and metaplasia of displaced embryonic pluripotent müllerian remnants (1). Adenomyosis can present as endometrial glands scattered throughout the myometrium or as a focal collection of endometrial glands, termed an adenomyoma.
Does low-dose aspirin use impact the menstrual cycle? A hypothetical risk gets debunked The use of daily low-dose aspirin by reproductive-age women has become increasingly common. Existing guidelines from the American College of Cardiology and the American Heart Association recommend low-dose aspirin for primary prevention of cardiovascular disease in high-risk women as young as 40 years of age (1). From a reproductive standpoint, low-dose aspirin is recommended for women at high risk for development of preeclampsia. It is also used with heparin to treat recurrent pregnancy loss in women with antiphospholipid syndrome.
Routine assessment of ovulation is unlikely to be medically necessary among eumenorrheic women Because ovulation induction is generally the first-line treatment target for couples with difficulty conceiving, existing recommendations regarding the role of ovulation testing among regularly menstruating women should be clear and evidence based. The American Society for Reproductive Medicine (ASRM) recommends ovulatory function assessment as part of the female subfertility workup without specification to menstrual history regularity, and the U.K.-based National Institute for Health and Clinical Excellence (NICE) recommends midluteal progesterone testing for confirming ovulation, even among regularly menstruating women.
Risk factors for uterine fibroids: time to build on what we have learned Uterine leiomyomata, or fibroids, are common, and symptomatic fibroids can severely reduce quality of life (1). Current medical and surgical treatment options are expanding but are frequently transient and may conflict with fertility plans. On this background of high prevalence, high symptom burden, and treatment options with potential adverse effects, the search for modifiable exposures to reduce fibroid prevalence is important. The recent investigation by Harris et al. (2), adds to the growing literature on the association of diet and fibroid risk.
Caution is warranted when discussing correlations between stress and reproductive outcomes It is well known that infertility patients experience stress and distress (e.g., depression or anxiety symptomatology) as a result of an infertility diagnosis or infertility treatment. However, less is known about the stress levels from planned oocyte cryopreservation (OC), and comparative studies are limited. The article “Differences in perceived stress during ovarian stimulation between women with infertility or pursuing oocyte cryopreservation” is a secondary analysis of the pre- and post-treatment self-reported stress levels of 165 first-cycle in vitro fertilization (IVF) patients and 52 OC patients who participated in the Learning from Online Video Education (LOVE) randomized controlled trial (RCT) (1).
Fluorescence-guided management of deep endometriosis To demonstrate the advantages of the fluorescence-guided surgery using indocyanine green (ICG) in the management of deep endometriotic nodules toward more complete and safe excision of the disease in cases when rectal shaving is performed.
Is Vitamin D important for IVF success? In this issue, Dr. Cozzolino and colleagues (1) have performed a systematic review and meta-analysis on the topic of the relationship between vitamin D serum levels and in vitro fertilization (IVF) outcomes. Their analysis determined that serum vitamin D levels have no significant effect upon IVF outcomes, as measured by clinical pregnancy rates, ongoing/live birth pregnancy rates, and/or miscarriage rates. This detailed analysis adds to the growing body of literature on the subject, and their conclusions are in clear contradistinction to at least one highly respected prior systematic review (2).
Infertility: a weight-bearing exercise? In this issue of Fertility and Sterility, Dr. Vitek and colleagues (1) outline compelling evidence that women with polycystic ovary syndrome (PCOS) gain weight during fertility treatment. This is important because Dr. Vitek pulls her data from the Reproductive Medicine Network’s Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation and Pregnancy in Polycystic Ovary Syndrome trials. Given the resources that fuel such trials, participants presumably have better access to reliable information, education, support, and follow-up than most women in need of fertility care.
Adults from donor-conceived families: some good news (from a longitudinal study) As many of us scan the Fertility and Sterility titles this month, we might go right by “Adult Offspring of Lesbian Parents” (1). Koh and colleagues’ article may seem peripheral to your practice or research, and few of us have time for other reading. But this article’s relevance is understated. If your focus includes donor conception and/or helping people have children, then donor-conceived (DC) adult views and experiences with their sperm donor may be able to tell us something more generally about donor-assisted families.
Embryo transfer training in fellowship: national and institutional data To evaluate current national practices in embryo transfer (ET) training in United States reproductive endocrinology and infertility (REI) fellowship programs and live birth rates after ET performed by fellows versus attending physicians.
Intergenerational programming and in vitro fertilization: another turn of the screw During human development, genome-wide epigenetic reprogramming occurs during gametogenesis and early embryo development, with epigenetic remodeling in somatic tissues continuing throughout prenatal development and into postnatal life. Based on the developmental origins of adult disease, these epigenetic events may be influenced by assisted reproductive technology (ART), which could alter embryonic and/or fetal growth trajectory to cause permanent physiological changes in offspring, thereby increasing the risk for cardiovascular disease in adulthood.
A genetic association study of kisspeptin 1/ neurokinin B systems in patients with infertility: Is it that simple? Genetic association studies are a useful tool for scientists to pinpoint potential culprit areas in the human genome that may be implicated in the pathogenesis of diseases. But is it that simple? How do you know whether the association is real? Does association mean causation? What if the results are negative? Can we say with certainty that the “interrogated” gene is “innocent”?
Adenomyosis and deep infiltrating endometriosis—how can disease severity be determined and correlated? In 1860, Carl Rokitansky, a Viennese pathologist, was the first to describe adenomyosis by examination of histological sections of the uterus and the rectovaginal space (1). Since then, many attempts have been made to elucidate the etiology and optimal therapy of adenomyosis and deep infiltrating endometriosis (DE), which have been described as commonly associated entities in several studies. The subsequent article of this group of authors, “Focal adenomyosis in the outer myometrium and deep infiltrating endometriosis severity” in this issue of Fertility and Sterility, provides further information on a possible link between focal adenomyosis of the outer myometrium (FAOM) and DE.
A question of the chicken or the egg In this scientific scavenger hunt, Santana et al. (1) aim to prove the hypothesis that men with varicoceles have unique epigenetic changes not seen in normal fertile patients. The authors’ data add to the growing body of evidence that DNA methylation patterns in sperm cells will inevitably be a measure to predict and to diagnose a spectrum of men’s health conditions. Santana et al. seek to identify changes in global sperm DNA methylation among men with and without varicoceles.
A septum is not always a septum: diagnosis and management of vaginal longitudinal septums via a video presentation The landmark study by Buttram and Gibbons (1) in 1979 recognized that the classification of müllerian anomalies is critically important for patient care yet challenging to refine. Since that publication, there have been ongoing attempts to produce clinically relevant classification systems (2, 3). However, to this day no one system is universally accepted. Although there are excellent reviews guiding surgical interventions for müllerian anomalies, to provide optimal care for their patients, clinicians must ultimately depend on a reliable method of assessment and categorization (4).
Fallopian tube endometriosis: clinical implications The recent publication by McGuinness et al. (1) regarding the incidence of fallopian tube endometriosis explores an issue relating to women with endometriosis that is not well investigated: what is the true incidence of both macroscopic and microscopic endometriotic lesions in the fallopian tubes of women undergoing minimally invasive surgery (MIS)? We are used to reading reports regarding the incidence of ovarian endometriosis or pelvic and even extrapelvic endometriosis. However, very little attention is given to the fallopian tubes and whether they may be affected by the disease.
Fibroids and medical therapy: bridging the gap from selective progesterone receptor modulators to gonadotropin-releasing hormone antagonist Uterine fibroids are the most frequent female pelvic tumors and the most frequent indication for hysterectomy, which is associated with morbidity rates of 5% to 8%. Undertaking a myomectomy is also not free of complication and alternative treatments, such as magnetic resonance–guided focused ultrasound and uterine embolization, are often proposed (1). However, there is still a need for medical therapy with the goal to postpone or avoid surgery in women wishing to do so and in women with fibroid-related infertility (1, 2).
Strategies to reduce multiple pregnancies during medically assisted reproduction Multiple birth rates after fertility treatment are still high in many countries. Multiple births are associated with increased rates of preterm birth and low birth weight babies, in turn increasing the risk of severe morbidity for the children. The multiple birth rates vary in different countries between 2% and 3% and up to 30% in some settings. Elective single-embryo transfer, particularly in combination with frozen-embryo transfer and milder stimulation in ovulation induction/intrauterine insemination, to avoid multifollicular development is an effective strategy to decrease the multiple birth rates while still achieving acceptable live-birth rates.
Man versus machine in IVF—can artificial intelligence replace physicians? Artificial intelligence (AI), the ability of machines to learn and display intelligence, is permeating all areas of medicine and promising to change clinical practice. Since the first attempt to use AI to predict pregnancy after in vitro fertilization (IVF) more than 20 years ago (1), investigations evaluating the possible use of AI in reproductive medicine are rapidly emerging. AI algorithms that analyze embryo and clinical parameters are being studied to improve IVF success (1).
The Lion King of ovulation induction Melvin Taymor’s daughter, Julie Taymor, directed the musical version of The Lion King, which won six Tony Awards. Known for her revolutionary staging, she became the first woman to be awarded a Tony for Best Direction of a Musical.
Cycle scheduling with oral contraceptives: Are we compromising rates for convenience? The debate over advantages and disadvantages of synchronization with oral contraceptives (OCPs) during in vitro fertilization (IVF) has persisted since the 2000s with the rise in popularity of GnRH antagonist cycles. A previous systematic review with meta-analysis showed lower live birth or ongoing pregnancy rates with OCP pretreatment in antagonist cycles with the combination of six randomized controlled trials (669 subjects in the treated group) (1). In the retrospective cohort study by Lu et al.
Do we need to consider human leucocyte antigen-C typing in infertility treatment? Given its high rates of implantation failure, spontaneous abortion, and placental insufficiency, human reproduction is a relatively inefficient process. In this issue of Fertility and Sterility the study by Alecsandru et al. (1) shows an evident association between paternal (or donor) human leucocyte antigen-C (HLA-C) genotype and both the live-birth rate and placental development. Their study follows on the research initiated in the 1940s after Ray Owen’s observations in cattle (2), which formed the basis for the concept of immunological tolerance and inspirations in reproductive biology for transplantation biology and, more specifically, reproductive immunology.
Diagnosing endometriosis in adolescents: ultrasound is a game changer Dysmenorrhea, the cardinal symptom of endometriosis in adolescents, is too often considered an unavoidable rite of passage that girls must soldier through to become a woman. The concept of primary dysmenorrhea with no anatomic cause embodies the paradigm that dysmenorrhea in adolescents is most often a non-material disorder. These beliefs are likely the root cause of the notoriously delayed diagnosis of endometriosis in adolescents. At the heart of the problem is also the reluctance to conduct diagnostic laparoscopy, the gold standard for diagnosing endometriosis, in adolescents for seemingly common symptoms such as dysmenorrhea.
Balancing innovation and safety: robotic-assisted donor surgery in uterus transplantation Since the first reported birth of a healthy child from uterus transplantation (UTx) in 2015, the number of reported births from clinical trials has been steadily increasing worldwide. The ethical issues surrounding UTx are complex and continuously evolving (1). Centers performing UTx use either living donors, deceased donors, or both. The advantages of a living donor model include the ability to perform a more thorough investigation of prospective donors and to optimize scheduling of procedures.
Finding a retained embryo after attempted embryo transfer: How does it impact outcomes? Discovering embryo retention (ER) after an initial embryo transfer (ET) has been reported as a rare but not uncommon outcome, occurring in 1% to 8% of ETs (1). Fortunately, with use of ultrasound guidance for ETs, the rate of ER has decreased (2). The impact of ER on pregnancy rates has varied, with some studies showing there is a decrease in pregnancy rates (3) while others have not found a statistically significant difference in pregnancy rates (1, 2, 4) when all embryos were successfully transferred on first attempt versus ETs that required multiple attempts.
Which medication and when should it be administered for reducing pain in intrauterine device insertion? Unintended pregnancy is a major health problem not only in undeveloped countries but also in the United States (1). The largest cohort study of intrauterine device (IUD) and implant users to date, in 2012, showed that the risk of contraceptive failure for those using oral birth control pills, contraceptive patch, or the vaginal ring was 17 to 20 times higher than the risk for those using long-acting reversible contraception (LARC) (1). Indeed, in the U.S. about 3 million pregnancies per year, half of all pregnancies, are unplanned and unintended, significantly more than in the other developed countries (1).
Autoimmune ovarian insufficiency: broadening indications for in vitro maturation Fertility preservation is a rapidly growing area in reproductive medicine, with oocyte vitrification after ovarian stimulation becoming a standard of care for women facing the imminent loss of their fertility, most commonly because of anticancer treatment. The short time frames involved for patient referral, counseling, and treatment, including the development of novel stimulation strategies, have led to the development of new skill sets within clinics that are largely based on existing approaches developed for patients attending for the treatment of infertility.
When do we use intracytoplasmic sperm injection? Intracytoplasmic sperm injection (ICSI), developed in the early 1990s, had become a routine part of in vitro fertilization (IVF) treatment at most assisted reproductive technology (ART) clinics by the late 1990s. Originally developed for severe male factor infertility, ICSI has assumed a role in treatment for many additional indications, including mild male factor infertility, history of failed fertilization, and unexplained infertility. However, at some clinics ICSI is used for additional indications—it may even be used in lieu of standard insemination for all cases.
Trophectoderm biopsy—perhaps not such a benign intervention In this issue of Fertility and Sterility, Lu et al. (1) conducted a retrospective cohort study to investigate whether the removal of a few trophectoderm cells during biopsy for preimplantation genetic testing (PGT) was associated with a decrease in serum human chorionic gonadotropin (β-hCG) level 12 days after transfer and/or any adverse perinatal outcomes. Comparison of clinical pregnancies after cryoembryo transfer of biopsied versus nonbiopsied single embryos showed that the biopsy group had statistically significantly lower mean β-hCG levels (703.1 ± 569.6 vs.
Introduction Randomized controlled trials (RCTs) and meta-analyses are the pinnacle of evidence-based medicine, enabling identification of the best available diagnostic, interventional, and therapeutic options. These tools help clinicians and policy makers to set clinical guidelines, but they also represent a double-edged sword: The meaningfulness of RCTs and meta-analyses relies on their quality, performance, and integrity. This Views and Reviews collection prepared by 18 renowned experts and coordinated by Ben Mol aims to inform and educate our readers about RCTs and meta-analyses in reproductive medicine.
Current evidence supporting a goal of singletons: a review of maternal and perinatal outcomes associated with twin versus singleton pregnancies after in vitro fertilization and intracytoplasmic sperm injection With increasing use of in vitro fertilization and intracytoplasmic sperm injection (IVF-ICSI) almost 2% of all babies born in the United States each year are now conceived with these technologies, making outcomes of IVF-ICSI extremely important not only to patients and families but to public health. Twin pregnancy rates after IVF-ICSI in the United States have declined since their peak in 2013 but remain at approximately 1 in 10 to 1 in 20 pregnancies. A review of the current international literature on twin versus singleton pregnancy outcomes after IVF-ICSI treatment confirms statistically significantly higher risks to maternal and perinatal health and statistically significantly higher health care costs.
Funding and public reporting strategies for reducing multiple pregnancy from fertility treatments The health of children born through assisted reproductive technologies (ART) is particularly vulnerable to policy decisions and market forces that play out before they are even conceived. ART treatment is costly, and public and third-party funding varies significantly between and within countries, leading to considerable variation in consumer affordability globally. These relative cost differences affect not only who can afford to access ART treatment, but also how ART is practiced in terms of embryo transfer practices, with less affordable treatment creating a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles.
Avoiding multiple pregnancies in assisted reproductive technologies: transferring one embryo at a time should be the norm Multiple pregnancies following fertility treatments typically occur in 30% of women in whom more than one embryo is transferred. Worldwide, fewer than 20 countries have fully funded public fertility treatments, and many women utilizing assisted reproduction technologies are transferring more than one embryo for financial reasons because they consider it will be cheaper to have two embryos transferred in the one procedure. Yet, there is a large body of evidence for the poorer health, economic, and social outcomes for mother and baby from multiple pregnancies.
An ounce of preimplantation prevention Benjamin Franklin famously reminded the citizens of Philadelphia that an “ounce of prevention is worth a pound of cure” when it came to the risk of fire. In this issue of Fertility and Sterility, authors from the same city have focused their attention on preimplantation genetic testing for monogenic disorders (PGT-M)–the ultimate form of prevention in reproductive medicine–by surveying patients to learn about barriers to its use. The application of PGT-M was predicted by Sir Robert Edwards even before the first successful in vitro fertilization (IVF) treatment and it has now been 30 years since the first successful use of PGT-M.
Conception, cerclage, and clinical counseling Procreative specialists have unique opportunities for primary prevention. The Barker hypothesis (1), where the intrauterine environment results in epigenetic influences beyond those contributed by maternal and paternal DNA, has important implications for preconception and antepartum care. Accordingly, reproductive endocrinologists counsel mothers-to-be regarding weight optimization, hypertensive control, diabetic management, and more because these can yield lifetime benefits for the future embryo and fetus.
Utility of gonadotropin-releasing hormone agonists for fertility preservation in women receiving chemotherapy: pros and cons The term “ovarian reserve” is typically used to refer to the population of primordial follicles (PMFs) (1). This population is very sensitive to cytotoxic drugs, especially alkylating agents (cyclophosphamide, busulfan, ifosfamide). Among them, cyclophosphamide (CPA) is the alkylating agent that causes the most damage to oocytes and granulosa cells (2). Alkylating-like platinum complexes (such as cisplatin, anthracyclanes [including doxorubicin]) should also be considered as ovo-toxic drugs.
Do we need to separate initiation and growth to understand endometriosis? A series of elegant experiments demonstrate that “epidermal growth factor (EGF) increases the expression of endometriosis-associated hyaluronan and its synthase hyaluronan synthase 2, both of which mediate EGF-induced stromal cell migration and invasion in women with endometriosis. These effects can be blocked by the pharmaceutical blocking of the EGF receptors. In addition serum EGF and hyaluronan levels are more elevated in women with endometriosis than in women without endometriosis, and the concentrations of hyaluronan correlate with EGF concentrations in all women” (1).
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