Diversity of international surrogacy arrangements: considerations for cross-border reproductive care As noted by Javda et al. in this issue of Fertility and Sterility, surrogacy is practiced in diverse ways (1). In gestational surrogacy, the woman who carries the pregnancy is solely a gestational carrier and has no genetic connection with the child. In contrast, with traditional surrogacy, a woman supplies her own eggs and also gestates the pregnancy, resulting in her and the resulting child having a genetic connection. Additionally, a surrogacy arrangement may be completely altruistic, in which the surrogate may be a friend or relative of the intended parents, or may be commercial, in which the surrogate is compensated for her services and may never meet the intended parents.
In vitro fertilization and infertility do not cause a significant alteration in placental gene expression at the end of the first trimester Pregnancies achieved after fertility treatments are associated with an increased risk of adverse outcomes such as compromised placentation, perinatal complications, and birth defects (1, 2). Moreover, studies using animal models indicate that assisted reproductive technology (ART) procedures could alter the epigenetic landscape of the preimplantation embryo when compared with embryos conceived naturally (3). These data lead to significant concerns regarding the safety of ART and therefore the health and well-being of individuals conceived using these technologies.
Introduction Surgical treatments offer effective solutions for many couples experiencing male factor infertility. This Views and Reviews collection of articles offers a state-of-the-art overview of the surgical procedures commonly used to treat impaired male reproductive health.
Letrozole versus clomiphene in polycystic ovary syndrome—more than one way to crack an egg Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. Optimal ovulation induction would achieve ovulation and live birth while minimizing the risk of multiple gestations, birth defects, side-effects, and cost. The optimal first-line agent has evolved based on several notable randomized controlled trials with surprising results. First, based on early data on the value of metformin for ovulation in PCOS, Legro et al. designed a randomized trial (RT) of extended-release metformin, clomiphene citrate (CC), or both to test the hypothesis that metformin would result in a higher live birth rate than CC and that the combination would result in a superior live birth rate (1).
What if deep endometriotic nodules and uterine adenomyosis were actually two forms of the same disease? Some symptoms of endometriosis, such as severe dysmenorrhea, overlap with those of uterine adenomyosis, a disease characterized by growth of endometrium into the myometrium. From a histologic point of view, deep rectovaginal endometriotic nodules were described by Donnez et al. (1) back in 1996 as “adenomyomas,” consisting of smooth muscle hyperplasia with active glandular epithelium and scanty stroma. In fact, the histologic patterns of deep endometriosis and uterine adenomyosis appear to be very similar.
Oocyte quantity and quality are crucial for a perspective of fertility preservation in women with Turner syndrome Affecting approximately 1 in 2,500 girls at birth, Turner syndrome (TS) is one of the most common chromosomal disorders, in which subjects are monosomic for the X chromosome (45,X) or, in a minority of cases, present with mosaicism for the simultaneous presence of a normal 46,XX cell line. TS is associated with a multiplicity of medical conditions and anatomic anomalies, including cardiac, circulatory, hepatic, renal, and metabolic pathologies, as well as short stature. TS also dramatically affects ovarian function and fertility.
Interplay of public perception and fertility guidelines Lee et al. (1) queried the public's perspectives on placing age limits on men and women seeking fertility treatment. Understanding the public's attitudes regarding management of infertility patients is relevant and necessary. Deviating significantly from what the public feels is acceptable puts infertility treatments in a bad light and generates a desire for government regulation. Unfortunately, when addressing technical issues of any nature, lay people, including legislators, often tend to jump to solutions before understanding the problem.
Optimizing office hysteroscopy Office-based diagnostic hysteroscopy has been developed to provide the necessary clinical information with minimal intervention. A cornerstone of this approach is that the woman's experience of this sensitive examination is acceptable to her and preferably pain free. Currently there is quite a range of opinions on the optimal approach to this, and this issue of Fertility and Sterility contributes by publishing a systematic review and meta-analysis on the efficacy of the opioid tramadol for pain relief during and after office diagnostic hysteroscopy (1).
Erratum In the article by Liu et al., “Comparison of the prevalence of chronic endometritis as determined by means of different diagnostic methods in women with and without reproductive failure” (Fertil Steril 2018;109:832-9), the units for Table 2 and Figure 2 in the section “Reference Range” under Results should read 10 mm2 and not 0.1 mm2. This typographical error does not bare any impact on the results or implications of the work. The authors apologize for this error.
Should the reproductive risk of a couple aiming to conceive be tested in the contemporary clinical context? In developed countries, single-gene diseases collectively account for 20% of infant mortality and approximately 10% of pediatric hospitalizations (34, 35). The ultimate aim of preconception carrier screening (PCS) panels is to increase the reproductive autonomy of individuals and couples by providing preconception knowledge that could inform them of the available treatment options. The options after PCS in general, and expanded PCS in particular, include preimplantation genetic testing for monogenetic disease (PGT-M), the use of gamete donors, conceiving without further testing after thorough genetic counseling, adoption, and refraining from having children (5).
Optimizing the opportunity for female fertility preservation in a limited time-frame for patients with cancer using in vitro maturation and ovarian tissue cryopreservation Increasingly patients are seeking the advice of reproductive medicine clinicians and scientists to enable them to preserve their gametes and/or embryos. The reasons are either as a form of reproductive insurance, or more important, to preserve their fertility before undergoing gonadotoxic therapy, most commonly chemotherapy. It is a guideline of the American Society of Clinical Oncology that all health care providers caring for adult and pediatric patients with cancer should address the possibility of infertility as early as possible before treatment starts (1).
Mitochondrial DNA copy number as a predictor of embryo viability The evaluation of embryo viability is typically based on morphologic and morphometric grading systems, which are known to be heavily affected by differences in subjective judgement. A significant proportion of euploid embryos do not implant even when the endometrium is normal, despite the wide incorporation of preimplantation genetic testing for aneuploidy. The need to improve reproductive outcomes following assisted reproductive treatments is culminating in the emergence of new research and technology with the potential to enhance embryo selection.
Adjusting for age: is it enough to just say you did it? The study by Gunnala et al. (1) examined an important and controversial question in the literature regarding the fertility potential of BRCA mutation carriers. As pointed out by the authors, determining whether or not carriers of the BRCA mutation have less reproductive potential when viewed from the standpoint of fertility preservation is important for counseling these patients because of their shortened reproductive window. Women with a BRCA mutation who may not be ready to start their families for various reasons have the option of fertility preservation through oocyte or embryo cryopreservation.
Tipping the scales for reproduction: a weighty problem “Dr. Chantilis, I'm sorry but I'm not able to get a completely accurate weight on your new patient because the scale only goes to 350 pounds, and oh, by the way, her husband is even larger,” said my medical assistant after obtaining vital signs on a new patient. As I walked into the consultation room, I encountered (even to this day after 27 years) the largest couple that I have ever seen. This visit is also indelible in my mind because the coasters on the husband's chair were bent and had to be replaced.
Mitochondria as a tool for oocyte rejuvenation Ovarian aging leads to a decrease in the quantity and quality of oocytes. Aged oocytes have significantly reduced amounts of mitochondria, the energy factories of cells, leading to lower fertilization rates and poor embryonic development. Various techniques have tried to use heterologous or autologous sources of mitochondria to reestablish oocyte health by providing more energy. However, heterologous sources are no longer used owing to the known risk of heteroplasmy. Although autologous methods have recently been tested in humans, they have not shown a clear improvement in embryo quality.
Vilaprisan phase 2B trial: a timely efficacy and safety study of a novel selective progesterone receptor modulator for nonsurgical management of uterine fibroids Uterine fibroids are benign hormone-sensitive tumors of the uterus that often affect women of reproductive age. Although many fibroids are asymptomatic, some women experience distressing symptoms such as heavy menstrual bleeding (HMB), pelvic pressure and/or pain, fertility impairment, and reduced quality of life. Hysterectomy is the definitive cure for uterine fibroids but is associated with complications and cannot be used if fertility preservation is important. Many women would rather avoid surgery and opt for uterus-preserving procedures (UPPs) or medical therapy.
Prediction of implantation after blastocyst transfer in in vitro fertilization: a machine-learning perspective To develop a random forest model (RFM) to predict implantation potential of a transferred embryo and compare it with a multivariate logistic regression model (MvLRM), based on data from a large cohort including in vitro fertilization (IVF) patients treated with the use of single-embryo transfer (SET) of blastocyst-stage embryos.
Is it time to start folate supplementation in men? The effect of paternal folate status on embryonic growth Maternal folate status is essential in normal embryonic growth, with deficits in folate resulting in neural tube and other developmental defects. The importance of maternal folate supplementation in preventing congenital malformations is evidenced in part by dietary folate fortification in countries like the United States. Although the relationship between a mother's diet and the long-term health of her offspring has been well studied, our understanding of how the paternal diet may affect fetal health remains limited.
Is antimüllerian hormone an early marker or an in utero effector of incipient polycystic ovary syndrome? Even when using the strictest of diagnostic criteria, the polycystic ovary syndrome (PCOS) affects almost 1 in 10 women worldwide. Although PCOS is most clinically evident during the reproductive age, it is also clear that PCOS is a complex genetic trait with lifelong consequences. However, the presentation and impact of PCOS at each of the extremes of reproductive life, in the peripuberty and the postmenopause, remains relatively understudied and less understood. We should recognize that the study of women as they age is critical to more precisely assess their risk, and the public health impact and preventive approaches, of their associated co-morbidities such as type 2 diabetes, cardiovascular disease, and malignancies.
Vitamin D, a promising natural compound with anti-uterine fibroid characteristics Uterine fibroids (UFs; leiomyomas) are benign monoclonal neoplasms of the myometrium and represent the most common tumors in reproductive-age women worldwide. Tumors occur in approximately 77% of women overall and are clinically manifest in approximately 25% by age 45 years. Although benign, these tumors are nonetheless associated with significant morbidity; they are the primary indication for hysterectomy and a major source of gynecologic and reproductive dysfunction, ranging from profuse menstrual bleeding and pelvic pain to infertility, recurrent miscarriage, and preterm labor.
Evidence-based medicine when the evidence is poor There have been many advances in the management of infertile men over the last two decades. Genetic causes of impaired spermatogenesis are routinely screened for in men with severe oligospermia and often are identified as the cause of a man's subfertility. Azoospermia due to impaired spermatogenesis was untreatable when I trained as a resident. Patients with nonobstructive azoospermia were told the only option to start a family was through donor insemination or adoption. We now can offer testicular sperm extraction and frequently find and use sperm for intracytoplasmic sperm injection.
Introduction This introduction reviews the background of mitochondrial transplantation. Its goals are to provide both basic and clinical insights into mitochondria and reproduction. The articles will review the biology of mitochondria, mitochondrial DNA, mitochondrial dynamics, and mitochondrial stress (unfolded protein response), discuss novel imaging technology, fluorescent lifetime imaging microscopy to visualize mitochondria and their function in oocytes and early embryos, provide a critical and objective review of the data suggesting and refuting the possible use of mitochondrial DNA as well as other emerging technologies as a biomarker for embryo viability and finally to review the use of mitochondria as a rejuvenation tool in human in vitro fertilization.
Metabolic imaging via fluorescence lifetime imaging microscopy for egg and embryo assessment Current strategies for embryo assessment in the assisted reproductive technology laboratories rely primarily on morphologic parameters that have limited accuracy for determining embryo viability. Even with the addition of invasive diagnostic interventions such as preimplantation genetic testing for aneuploidy alone or in combination with mitochondrial DNA copy number assessment, at least one third of embryos fail to implant. Therefore, at a time when the clinical benefits of single ET are widely accepted, improving viability assessment of embryos is ever more important.
Demystifying “mosaic” outcomes The use of preimplantation genetic testing for aneuploidy (PGT-A) has increased in recent years following the publication of trials demonstrating improved outcomes per transfer in good prognosis patients (1). Though not used in those trials, the PGT-A field rapidly adopted next generation sequencing (NGS) as the most common method. Cell line studies demonstrated that NGS can more reliably predict whether a model embryo biopsy contains a mix of normal and abnormal cells, leading to the mosaic diagnosis becoming part of the PGT-A lexicon.
Mitochondrial unfolded protein response: a stress response with implications for fertility and reproductive aging Mitochondria play a central role in the regulation of energy metabolism in oocytes and preimplantation embryos, where the number and morphology of mitochondria and mitochondrial DNA (mtDNA) content are tightly regulated. A number of mouse models with mitochondrial dysfunction result in infertility, further confirming the key role of mitochondria in female reproductive function. When cells and organisms detect mitochondrial dysfunction they use response mechanisms directed at recovering salvageable mitochondria and eliminating mitochondria that can no longer be rescued.
Opportunities and challenges for population-based studies investigating the effects of air pollution on pregnancy loss Pregnancy loss occurs to approximately 28% of all pregnancies in prospective cohorts of couples attempting pregnancy (1). There is also evidence that the rate of self-reported pregnancy loss has been increasing in the United States (2). The exact cause of pregnancy loss is unknown, making it difficult to design effective interventions, and many losses are unobserved by couples or the medical care system, making ascertainment challenging outside of select prospective studies. Nevertheless, there is evidence that in addition to intrinsic factors like genetics, the risk of pregnancy loss can also be driven by extrinsic factors that are potentially amendable to intervention.
Future fertility in survivors of childhood cancer—examining the impact of cancer treatment on uterus function The worldwide population of survivors of childhood cancer is increasing. In Europe, current estimates are that there are nearly 500,000 childhood cancer survivors with a median age range between 25 and 29 years. Approximately 10,000 new survivors are added to these numbers on a yearly basis (1). The U.S. cancer statistics report of incidence, mortality, and survival from the American Cancer Society has also confirmed a sustained increase in the 5-year relative survival rate of children and adolescents treated for all cancer diseases combined.
Early phenotypes in polycystic ovary syndrome: some answers, more questions Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with poor reproductive outcomes, including infertility and pregnancy complications, and poor metabolic outcomes, including insulin resistance, type 2 diabetes, and the metabolic syndrome. Prevalence estimates for PCOS range from 7% to 15% of reproductive-age women worldwide, depending on the diagnostic criteria used. Accordingly, PCOS-associated dysglycemia and obesity are a global public health risk. Despite the public health importance of PCOS, notable gaps exist in the literature regarding its pathophysiology, natural history, and optimal management.
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