Functional impairment of common gynecologic diseases in the “Me Too” era The functional impairment of common gynecologic diseases is astounding. Women have likely curtailed their activities due to pelvic pain or heavy and unpredictable menstrual bleeding for centuries. However, women increasingly work outside the home or are the main or sole wage-earner for a family, which makes it easier to quantitate the economic impact of this impairment. Although the article by Pokrzwinski and colleagues (1) in this issue of Fertility and Sterility focuses on endometriosis and the investigational oral GnRH antagonist elagolix, there are a number of more generalizable issues that it addresses.
Endometriosis: a complex systemic disease with multiple manifestations Endometriosis has long been considered a disease localized to the pelvis with pain as the primary manifestation. Often overlooked are the multiple subtle manifestations of the disease. The immediate need for pain relief typically is the primary focus of the patient and physician. Numerous symptoms in addition to pain contribute to the burden of this disease. Here Surrey et al. (1) focus on one symptom that is frequently disruptive to patients with endometriosis. Fatigue is infrequently used as an end-point in clinical trials, however fatigue can be a debilitating symptom of endometriosis.
Benefits of pregnancy on endometriosis: can we dispel the myths? Regression of endometriotic lesions during pregnancy was first described by Sampson in 1921. Since that time pregnancy has often been recommended by health professionals as a useful strategy to reduce disease progression and symptoms. Lack of symptoms before menarche and after menopause, both associated with amenorrhoea, further supported the hypothesis that pregnancy was beneficial. Progesterone induces endometrial atrophy and endometriotic lesions show cyclic changes such as endometrial growth and luteal transformation throughout the menstrual cycle.
Pregnancies in women with Turner Syndrome: how do we counsel our patients? In this issue of Fertility and Sterility, the Fertile Battle debate focuses on the question of how best to counsel patients with Turner Syndrome (TS) regarding their options for pregnancy. Most patients with TS experience ovarian failure prior to menarche, but with egg donation, they can successfully conceive and carry the pregnancy to term, albeit with significantly increased obstetrical risks. The question is, are these risks so high that gestational surrogacy should routinely be advised? Are the risks so high that embryo transfer to the uterus of a TS patient should not even be considered? Are there screening methods that might divide the potential population into those individuals whose underlying cardiovascular risks are too high to allow pregnancy and those who might reasonably be monitored and guided by a skilled perinatologist through a high-risk pregnancy?
T-shaped uterus and subtle uterine variances: a need for reliable criteria The ASRM Class VII, the ESHRE/ESGE Class U1 and the T-shaped uterus have a uniquely interesting history. The T-shaped uterus was first described as a diethylstilbestrol- (DES-) related congenital uterine anomaly based on findings from hysterosalpingography by Kaufman in 1977. Together with two similar morphologic forms of the uterus—constricting bands in the uterine cavity and a widening of the lower two-thirds of the uterus—this was included as a separate class of DES-related anomalies by the Buttram and Gibbons 1979 classification, and its further modification—the American Fertility Society classification.
Old is bad, young is good but what about very young? Oocytes obtained from pre-pubertal ovarian tissue of very young patients are incapable of in vitro maturation Currently, the only fertility preservation option for prepubertal girls is storage of ovarian cortical tissue with the potential for reimplantation later in life. The excellent cancer survival rates of prepubertal children after chemo/radiotherapy are somehow diminished in value by the limited options available for preserving future fertility. The paper by Karavani and colleagues (1) in this issue expands much needed research in pre-menarche ovarian and follicle physiology by exploring the maturation competence of immature oocytes harvested from the ovarian cortex of prepubertal girls.
Laparoscopic approach to cornual ectopic: a step-by-step demonstration To concisely review what is known about cornual ectopic pregnancies and to provide a step-by-step demonstration of the resection of a large cornual ectopic pregnancy, highlighting various laparoscopic techniques.
Nurses are an asset to an in vitro fertilization program, and more so if they are continually educated As part of the objectives set out in the Patient Protection and Affordable Care Act of 2010, the Institute of Medicine (IOM) published in its report on the future of nursing (1) a section entitled “The Future of Nursing: Leading Change, Advancing Health.” Within that section, the committee recognized the need to focus on higher education for nurses, specifically to promote “lifelong learning” and “the need for highly educated nurses” (1). According to the World Health Organization (WHO), nurses account for nearly 50% of the global health workforce (2), and within the United States there is a projected need for an additional 203,700 nurses each year through 2026 (3).
Sperm DNA fragmentation to predict embryo development, implantation and miscarriage: still an open question Male factor infertility is responsible for approximately half of all causes of infertility. In the last decade, more attention has been given to sperm DNA fragmentation (SDF) as a potential cause of unexplained infertility. The increased DNA damage in spermatozoa from men with oligozoospermia seems to be associated with both a reduced chance of natural conception and an increased risk of early pregnancy loss (1). Nevertheless, the role of SDF during in vitro fertilization cycles where intracytoplasmic sperm injection (ICSI) is adopted is still unclear.
In pursuit of understanding interstitial pregnancies: a rare yet high-risk ectopic pregnancy Implantation of an embryo in the interstitial portion of the fallopian tube leads to an ectopic pregnancy that has an alarming mortality rate of 2.5% (1), seven times greater than that of ectopic pregnancies in general. The difficulties associated with the diagnosis and the surgical skill required for treatment make management of interstitial ectopic pregnancies extremely challenging. Once thought to account for 2% to 4% of all tubal pregnancies, the incidence of interstitial ectopic pregnancy is now up to 7.3% (2) and has been reported to be as high as 35.5% of all ectopic pregnancies after in vitro fertilization (3).
A case for the gonadotropin-releasing hormone-agonist trigger in every freeze-all cycle? This Reflections is a commentary on an excellent study by Thorne et al. (1) whose group of investigators has long-standing experience with the use of gonadotropin-releasing hormone (GnRH)-agonist triggers in in vitro fertilization (IVF) and who pioneered much of the work on luteal support for fresh embryo transfer in GnRH-agonist triggered patients. In this study, the authors compared euploidy rates following preimplantation genetic testing for aneuploidy in IVF cycles in which final follicular maturation was triggered by human chorionic gonadotropin (hCG) to those cycles in which the trigger was a GnRH-agonist (1).
When to jump-start fertilization The implementation of intracytoplasmic sperm injection (ICSI) has enabled men with even the most severe forms of male factor infertility to achieve fertilization and pregnancy—something that had not been possible with conventional in vitro fertilization. With its ability to attenuate defects of the zona pellucida and sperm acrosomal dysfunction, ICSI has become very popular, making it a suitable assisted reproductive technology technique for a variety of infertility indications. However, although rare, some couples suffer from total fertilization failure even with the use of ICSI.
Unraveling the biologic and social predictors of infant sex among assisted reproductive technology cycles in the United States As assisted reproductive technology (ART) has evolved over the past decades, there has been an increase in the use of ART worldwide, as well as the use of different techniques, including intracytoplasmic sperm injection (ICSI), extended culture, and preimplantation genetic testing (PGT). In this issue of Fertility and Sterility, Narvaez et al. provide an important update on how the use of ART in the United States and the practices specific to ART may be altering the sex ratio (1). She and her coauthors used data from the Centers for Disease Control National Assisted Reproductive Technology Surveillance System (NASS) to assess trends and characteristics associated with a male-biased sex ratio in live-born infants among all ART cycles from 2006 to 2014.
Gene expression and lifestyles In recent years, it has become increasingly evident that lifestyles, understood as diet, obesity, working habits, physical activity, and smoking, affect human health. Complex diseases such as cancers, diabetes, and neurodegenerative disorders are due to multiple gene mutations associated with environmental factors; therefore, they depend on close genome–environment interactions. The primary mechanisms by which the environment influences the genome are epigenetic modifications, such as DNA methylation and histone posttranslational regulation (1).
Evolving insights into the relationship between miR-23a/b-3p and target genes in subfertile patients Spermatogenesis is a complex, highly regulated process by which spermatogonial stem cells replicate and develop into spermatozoa (1). A series of specialized differentiation events in the seminiferous tubules facilitate the spatial and temporal progression into functional sperm. Consequently, aberrations in these testicular regulatory mechanisms and gene expression patterns can contribute to male infertility. Our understanding of the genetic underpinnings of male infertility continues to evolve as new biomarkers for the condition are discovered.
The preimplantation genetic testing debate continues: first the hype, then the tension, now the hypertension? The study by Zhang and colleagues (1) in this month's Fertility and Sterility asks an important question: Is preimplantation genetic testing (PGT) associated with an increased risk of obstetric complications? Given the physiologic role of the trophectoderm in implantation, invasion, and placentation (2), it seems biologically plausible that manipulation of these cells through biopsy sampling could result in an increased risk of aberrant placentation. The rapid increase in the clinical use of PGT further justifies more scientific inquiry into this question.
Health status of young adults conceived by assisted reproductive technology: is there cause for concern? Although pregnancy outcomes among conceptions with assisted reproductive technology have received considerable attention recently (1, 2), longer-term health, developmental, educational, psychosocial, and socioeconomic outcomes are less well studied. In part, this reflects the relative recentness of developments in the field of reproductive endocrinology, but now, as the second decade of the 21st century comes to a close, we have more than 40 years of experience to reflect on. The study by Halliday et al.
Subtypes of T-shaped uterus To present three different subtypes of T-shaped uterus with the use of three-dimensional (3D) ultrasound imaging and hysteroscopy.
DNA methylation profiling of peripheral blood samples is a promising new approach to screen for male infertility Male infertility is a complex, multifactorial, and heterogeneous condition. In ∼15% of couples, infertility results from an identifiable genetic defect. However, in 40% of couples, male infertility is likely to be caused by an unknown genetic abnormality. Consequently, many men evaluated for infertility may not ultimately be diagnosed beyond the phenotype of their infertility, such as azoospermia or maturation arrest. Emerging research into the mechanisms underlying idiopathic male infertility promises new opportunities to provide these men with more specific diagnoses.
Discordant ovarian reserve testing: what matters most? When counseling patients planning in vitro fertilization (IVF), predictors of both potential oocyte yield and likelihood of live birth are invaluable. Reproductive endocrinologists have used antral follicle counts, basal follicle-stimulating hormone (FSH) levels, and antimüllerian hormone (AMH) values to predict diminished ovarian reserve (DOR), a poor response to ovarian stimulation (1). DOR is associated with increased risks of IVF cycle cancellation, lower oocyte yield, and less embryos available for transfer and cryopreservation.
Primum non nocere: are we closer to saying that the trophectoderm biopsy does no harm? Every year the Centers for Disease Control and Prevention (CDC) publishes its Assisted Reproductive Technology (ART) National Summary Report, and every year the total number of ART cycles have been steadily increasing. In 2016 the total number of cycles rose to over 263,000, which was almost double the number of cycles in 2007. The increase in cycle number has come with a broader social acceptance of the technologies involved, as well as increased access to these technologies. More recently, there has been a dramatic rise in the use of preimplantation genetic testing (PGT) (previously designated as preimplantation genetic diagnosis/preimplantation genetic screening).
Optimizing semen parameters at the molecular level: possible avenue for improvement in assisted reproductive technology success rates? One of the major indications for the use of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is the presence of significantly impaired semen parameters in the male partner. These impaired parameters are typically ones that are evaluated via a routine semen analysis, such as sperm concentration and motility, as well as laboratory indicators of underlying abnormalities, such as antisperm antibodies (sperm agglutination). However, despite the ability to place a single sperm into an ovum, bypassing several potential barriers to fertility, assisted reproductive technology (ART) live birth rates are at best 30%, with this number decreasing substantially with advanced maternal age (1).
Maternal and neonatal outcomes associated with trophectoderm biopsy To assess whether pregnancies achieved with trophectoderm biopsy for preimplantation genetic testing (PGT) have different risks of adverse obstetric and neonatal outcomes compared with pregnancies achieved with IVF without biopsy.
In vitro maturation rates in young premenarche patients To evaluate in vitro maturation (IVM) efficacy and oocyte retrieval rates after ovarian tissue cryopreservation in young premenarche girls facing chemo- and radiotherapy.
Laparotomy or minimal invasive surgery in uterus transplantation: a comparison Uterus transplantation (UTx) is the first available treatment for absolute uterine factor infertility, a condition due to absence of the uterus or presence of a non-functional uterus. The proof-of-concept of UTx as an infertility treatment for this group of patients occurred in 2014 in Sweden by the first birth after human UTx. That and subsequent cases of the Swedish trial were live-donor UTx procedures with laparotomy of both donor and recipient. Although results of the initial Swedish clinical UTx trial were very favorable in terms of take-home-baby rate, the drawback was the long duration (>10 h) of donor surgeries and associated long recovery periods.
Introduction Uterus transplantation is the first available treatment for absolute uterine factor infertility. Live births have been reported after transplantation of uteri both from live and deceased donors. Although this novel infertility treatment is still at its experimental stage, with human attempts performed within clinical trials, there is a rapid development in the field. Up until June 2019 more than 60 human uterus transplantation attempts have been performed and the scientific data of the published cases will be reviewed in relation to surgery and outcome.
Global results of human uterus transplantation and strategies for pre-transplantation screening of donors Absolute uterine factor infertility, due to absence or non-function of the uterus, is one of the few major subgroups of infertility that has remained without any treatment. Uterus transplantation has now been proposed as treatment for this type of infertility. The first attempt of human uterus transplantation was in 2000. This was a live donor case, but due to suboptimal surgical solutions it resulted in a necrotic uterus being removed after 99 days. This first human case, although a failure, inspired several research groups around the globe to initiate animal-based studies to investigate uterus transplantation in relation to surgery, immunosuppression, rejection and pregnancy outcome.
Live versus deceased donor in uterus transplantation Uterus transplantation to treat absolute uterine factor infertility is a rapidly evolving field still at its early clinical experimental stage. Most human uterus transplantation attempts and live births have been after transplantation with uteri from live donors, who, in most cases, are closely related to the recipient. However, successful transplant with live births after uterus transplantation from deceased donors has also been reported. This article discusses the pros and cons in relation to live and deceased donors for uterus transplantation.
Assisted reproductive technology strategies in uterus transplantation The development of assisted reproductive technology (ART) through four decades has led to offer the ultimate treatment for nearly all forms of infertility. The only remaining factor of childlessness however that still eludes ART and its routine variants are the absolute uterine infertility factors, for which the only option is an experimental approach, uterus transplantation. Progresses has been made over the past few years, and more are underway for simplifying the process notably for simplifying the uterus extraction step performed in the uterus donor.
Artificial intelligence: its applications in reproductive medicine and the assisted reproductive technologies At its core, artificial intelligence (AI) is “a partnership between man and machine” (Ginni Rometty, IBM CEO). The embodiment of AI is a computer program that can learn to execute tasks involving forms of intelligence normally ascribed to humans. How well a computer will be able to emulate or exceed humans is the essential question driving AI technology.
Ovarian antimüllerian hormone system: more complex than was thought The antimüllerian hormone (AMH) in blood may present in different isoforms. In women it is secreted by ovarian granulosa cells as a pre-pro-protein and after the removal of the signaling sequence it turns to a proprotein called proAMH. It is believed that the proAMH cannot bind to the AMH specific receptor (AMH receptor type 2, AMHRII). A successive proteolytic cleavage of the proprpotein occurs and leads to the generation of the amino terminal (AMHN) and carboxy –terminal dimer (AMHC). These two peptides are nonconvalently associated (AMHN,C) and the formation of a complex between the two increases solubility of the peptides, hence facilitating their diffusion to tissues and cells (1, 2).
Need for expanding insurance coverage for in vitro fertilization in the United States In this issue, Bedrick and colleagues (1) examine factors associated with discontinuation of in vitro fertilization (IVF) treatment and time to return for a second IVF cycle (1). The authors found that the three groups most likely to discontinue IVF treatment and have a longer time of return to treatment were patients without insurance coverage for IVF, African American women, and older women with a poor prognosis. Women without insurance coverage for IVF had a three-hold higher odds of treatment discontinuation in comparison to patients with access to insurance coverage.
Is coffee bad for reproduction? Maybe not, after all. Coffee has a long history of being considered as a potential culprit for nearly every single human malady. Over the past decades, coffee drinking, the most important source of caffeine, has been suggested as a risk factor for cancer, heart disease, and every other common chronic disease, not to mention pregnancy complications and other adverse reproductive events, from infertility and pregnancy loss to preterm birth and adverse perinatal outcomes. Considering caffeine as a potentially harmful substance is not entirely without merits.
Original investigations into the effects of testicular biopsy Testicular biopsy appears to enhance sexual function and to influence hormonal output. Stimulation of sexual function seems to be the earliest and most characteristic response to the operation and is probably attributable mainly to nervous stimulation.—Georgescu et al. 1969
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