Seeking the elusive genes associated with varicocele: a step forward It is well established that varicocele can harm testicular function and fertility, mainly through thermal damage and oxidative stress (1). However, the reasons why the disease affects each individual’s fertility in differing ways are not entirely understood. Moreover, the exact genetic background of familial varicocele and whether genetic factors increase the predisposition to varicocele occurrence are unknown. The multiplicity of phenotypes associated with varicocele suggests a complex multifactorial disorder in which genetic, epigenetic, and environmental factors seem to play a decisive role (1, 2).
Is in vitro fertilization the answer in polycystic ovary syndrome? After several cycles of unsuccessful clomiphene citrate induction, offering in vitro fertilization (IVF) to patients with infertility related to polycystic ovary syndrome (PCOS) is standard practice. With the rising rates of IVF success in many cases of unexplained infertility, the costs—monetary or otherwise—of IVF are accepted by both patients and health care providers. However, even with carefully standardized protocols, we still often find that PCOS patients with an especially high body mass index (BMI) struggle with achieving clinical pregnancy and have lower live-birth rates (1).
Mayer-Rokitansky-Küster-Hauser syndrome associated with fused renal ectopia and hydroureter The video presentation entitled “Mayer−Rokitansky−Küster−Hauser syndrome with rare findings of crossed-fused renal ectopia and Gartner’s duct cyst: a video case report” presents treatment of vaginal agenesis and reimplantation of hydro-ureter into the bladder (1). This is a wonderful report of a rare combined Müllerian and renal anomaly, and highlights the diverse spectrum of anomalies that exist. The video presentation is a nice demonstration of the Davydov procedure, with a detailed step-by-step depiction of dissection in the vessico-rectal space to create a neovaginal space.
Improving access to procreative care through affordable hysteroscopic myomectomy Enhanced access to procreative care resonates with patients and clinicians. This stems from our belief in justice and equity. Ethics teaches us that high-quality healthcare should be a right, and not just a privilege for the economically fortunate few. Our American Society for Reproductive Medicine (ASRM) Ethics Committee guidelines acknowledge this reality by noting, “Economic barriers are the chief contributors to disparities in access to effective treatment” (1). Although acknowledging the need for research on biological causes of infertility, such as fibroids, polycystic ovary syndrome, and azoospermia, these particular guidelines emphasize assisted reproductive technology (ART) as the solution.
Legal considerations in reproductive medicine Legal issues affect reproductive medical practice throughout the entire world. The breadth and depth of this interrelationship extend far beyond the scope of one series of articles in Views and Reviews. Given this limitation, we have chosen to present five topics, all different, but illustrative of key concepts that influence our practice of reproductive medicine. Our hope is that this “medical-legal sampler” will both inform and provoke thoughtful consideration of the ways we can best and most responsibly practice and serve our patients.
Emerging therapies for endometriosis Although endometriosis is one of the most common gynecologic diseases, treatment options have long been limited. Commonly used medications include nonsteroidal antiinflammatory drugs, progestins (including those in oral contraceptives), danazol, and GnRH agonists. Danazol and GnRH agonist use are associated with significant side-effects. Progestins use may also result in side-effects, including mood changes, breakthrough bleeding, breast tenderness, and bloating. Furthermore, progestins are not always effective; progestin resistance is common, occurring in 30%–50% of women using progestin-based therapies for endometriosis (1).
An oncofertility prediction tool? Forecasting fertility after cancer As cancer survival rates increase among adolescents and young adults, the need for fertility preservation awareness and counseling has grown in parallel. Although general negative predictors of future fertility after cancer treatment are recognized, Hopeman et al. (1) further define the risk associated with certain clinical variables—including age, cancer diagnosis, and chemotherapy treatment—in their prospective cohort study, “A Predictive Model for Chemotherapy-Related Diminished Ovarian Reserve in Reproductive-Aged Women.”
In vitro maturation: a committee opinion The results of in vitro maturation (IVM) investigations suggest the potential for wider clinical application. This document discusses the efficacy of IVM as reported in the published literature to date. This document replaces the document of the same name, last published in 2013.
The heart of the matter: balancing potential cardiovascular risks with known benefits of gender-affirming testosterone Over the past few years, as visibility and acceptance of gender diversity have increased, the number of people identifying as transgender or nonbinary has been rising. Based on 2015 data, transgender people comprise 0.58% of the adult U.S. population, or about 1.9 million people. A large majority of transgender people (78%) express interest in, or are currently using, gender-affirming hormones (1). However, there is little long-term safety data on the use of gender-affirming hormones, and recommendations and counseling are often extrapolated from studies in hypogonadal men, postmenopausal women, and women with polycystic ovary syndrome.
Fertility—a human right worthy of mandated insurance coverage: the evolution, limitations, and future of access to care We review the history, current status, and potential future of state infertility mandates and focus on the business implications of mandates and on the inadequacies and reproductive injustice resulting from gaps between legislative intent and practical implementation. Nineteen states have passed laws that require insurers to either cover or offer coverage for infertility diagnoses and treatment. The qualifications for coverage, extent of coverage, and exemptions vary drastically from one state to another, resulting in deficiencies in access to care even within mandated states for certain groups, such as single individuals, patients in same-sex relationships, and patients pursuing fertility preservation.
My mama had endometriosis Endometriosis continues to wear “many hats” in the lives of women and the physicians who care for them. Not referenced here is the progress that has been made in understanding the pathophysiology of the disease and the pain and infertility that result. The article by Tuominen et al. compares obstetrical outcomes in a relatively large number of women presenting with rectovaginal endometriosis (RVE) (1). On review of the literature, there are studies highlighting specific pregnancy outcomes from women with RVE and comparing reproductive success in women with RVE treated with either conservative management or surgery, but none specifically comparing pregnancy outcomes from patients with RVE receiving either surgery or conservative management.
Diagnosis and treatment of infertility in men: AUA/ASRM guideline part II The summary presented herein represents Part II of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part II outlines the appropriate management of the male in an infertile couple. Medical therapies, surgical techniques, as well as use of intrauterine insemination (IUI)/in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) are covered to allow for optimal patient management. Please refer to Part I for discussion on evaluation of the infertile male and discussion of relevant health conditions that are associated with male infertility.
Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I The summary presented herein represents Part I of the two-part series dedicated to the Diagnosis and Treatment of Infertility in Men: AUA/ASRM Guideline. Part I outlines the appropriate evaluation of the male in an infertile couple. Recommendations proceed from obtaining an appropriate history and physical exam (Appendix I), as well as diagnostic testing, where indicated.
Basics of practice management: managing many for the care of one In today’s changing health care landscape, it has become necessary that providers have a fundamental understanding of practice management as pertinent to the care they provide. The reproductive endocrinology and infertility (REI) practice is a uniquely complex setting with many component parts, necessitating frequent assessment and collaboration to provide safe, quality, and cost-effective care. In this review, we aim to describe the basics of medical practice management, divided into six sections: practice models; operations; patient safety; patient experience; employee recruitment; development, and satisfaction; and technology.
Financial fluency: demystifying accounting and business planning for the reproductive medicine specialist In today’s ever-changing business climate, reproductive health specialists are realizing that financial fluency is key to growing and maintaining a successful practice. Although financial fundamentals such as accounting may seem complex, both academic and private practice reproductive specialists who understand these topics can benefit in making business decisions for their practices. We describe the key financial fundamentals that reproductive health specialists should know, including basic concepts of finance and accounting, payments and receivables, capital budgeting, and business planning, and interpreting balance sheets, income statements, and cash-flow statements.
Back to the basic science of fertility One day later, there was a marked increase in the vascular supply of the testis, and numerous vessels appeared to have breached the membrana propria of the tubules.Kochar NK, Harrison RG. The effects of x-rays on the vascularization of the mouse testis. Fertil Steril 1971;22:53‐57.The impact of temperature shock upon mammalian sperm is severe, and produces physical as well as biochemical alterations in the cells.Ackerman DR. Variation due to freezing in the citrate acid content of human semen. Fertil Steril 1971;22:58–60.
Delving deep into excision of bowel endometriosis Endometriosis is a chronic, benign gynecologic disease characterized by implantation of endometrium-like tissue outside of the uterus. Pathogenesis is complex and likely multifactorial with environmental, genetic, epigenetic, immunologic, and other unknown factors contributing to development of disease. It is present in an estimated 6%–10% of reproductive-aged women and may present with a variety of symptoms and phenotypes. Although some women are asymptomatic, others may suffer from painful menses, dyspareunia, infertility, dyschezia, painful bladder symptoms, and chronic pelvic pain.
Umbilical cord blood–derived platelet-rich plasma: a clinically acceptable substitute for fetal bovine serum? Platelet-rich plasma (PRP) is derived from blood and constitutes a plasma fraction with a concentration of platelets 3–5 times higher than in blood. On activation, platelets release a multitude of growth factors in high concentrations, including members of the transforming growth factor β superfamily, platelet-derived growth factor, insulin-like growth factors, vascular endothelial growth factor, basic fibroblast growth factors, hormones, and cytokines related to tissue repair, angiogenesis, and regeneration.
Polycystic ovary syndrome and preterm birth—what’s going on? Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders worldwide and a leading cause of female infertility. With the advent and increasing use of assisted reproductive technology (ART), women with PCOS are having children at a rate similar to that of women without PCOS. However, a PCOS diagnosis and ART treatment have each been associated with adverse maternal and neonatal outcomes. Teasing out the associations specific to PCOS from those specific to treatment processes is difficult in a population setting.
Ureteral endometriosis requiring bilateral ureteroneocystotomy: saving the endangered kidneys As I watch the video of Fernandes et al. on laparoscopic bilateral ureteral reimplantation for ureteral endometriosis (1), it brings to mind one of the central themes of the movie Saving Private Ryan. Similar to how the war had killed three of the four sons within the same family, and the fourth son was in imminent danger, endometriosis had affected different organs of the reported patient and was endangering her kidneys. Endometriosis has been estimated to affect approximately 10%−20% of reproductive-aged women and can cause significant loss of function in multiple organs.
Evaluating recurrent implantation failure in the setting of euploid elective single-embryo transfer: Is three really the magic number? Conventional wisdom has held that the health of the oocyte and the quality of the resulting embryo after fertilization are the most important factors in fertility. The well-documented decrease in female fertility with increasing age is directly tied to the inverse relationship between age and egg quality. The number one culprit is thought to be genetic abnormalities arising from errors as the oocyte awakens from its long slumber. By eliminating the variable of aneuploidy, through the limitation of frozen embryo transfers (FETs) only to known euploid embryos, Pirtea et al.
Vitamin D and uterine leiomyomata: is it time to let the sunshine in? In this issue of Fertility and Sterility, Corachál et al. (1) examine one aspect of the accumulating evidence suggesting that the vitamin D signaling pathways are attractive targets for prevention and treatment of uterine leiomyomata (fibroids). Vitamin D is a unique secosteroid prohormone in that it can be obtained through dietary intake and can be synthesized in skin from exposure to sunlight. Vitamin D also requires sequential hydroxylation in the liver and kidney to assume its active form, 1,25-dihydroxy vitamin D.
Are we adaptable? The Zoom platform was founded in April 2011. Online meetings were something we knew of, participated in for certain settings, but “in-person” attendance was the gold standard prior to approximately March 2020. Flash forward to our mid–COVID19 pandemic lives and we see the stark comparison with the expectations that are now in place for meetings, grand rounds, educational sessions, and even conferences (virtual conferences…who would have ever thought!). Coronavirus changed the way we use the internet with movement to use of Zoom, Google Classroom, Google Hangouts, Microsoft, and many others for communication that allows us to achieve our goals (1).
Transforming growth factor β–sphingosine 1-phosphate axis in pathogenesis of endometriosis Endometriosis is characterized by the presence of endometrial cells and tissue outside the uterine cavity. It is an inflammatory disorder affecting up to 10% of women of reproductive age. The most common symptoms are chronic pelvic pain and infertility potentially due to adhesions and fibrosis, which may lead to anatomical distortions resulting in infertility. Fibrosis, the replacement of normal parenchymal tissue by connective tissue, can result from chronic inflammatory reactions (e.g., in response to lesions), forming permanent scars with resistance to pharmacologic treatments.
Finding the needle in the haystack Preoperative identification of the rare and deadly uterine sarcoma in a woman with presumed uterine fibroids can be like trying to finding a needle in a haystack. This issue of detecting occult uterine malignancy when both sarcomas and fibroids present as a uterine mass highlights the particular challenge of designing and validating a screening test for a disease with low underlying prevalence. As synthesized in the 2017 systematic review and meta-analysis commissioned by the Agency for Healthcare Research and Quality, data from 160 studies found that the risk of discovering a leiomyosarcoma at the time of surgery for presumed fibroids is 0.02% based on prospective studies, and 0.08% based on retrospective studies (1).
Expanding our knowledge of premature ovarian insufficiency Premature ovarian insufficiency (POI) has received increasing attention over the past two decades as it has become apparent that this is not an extremely rare disorder. Our thoughts about this disorder have evolved, just as has the name given to the disorder itself. As noted by others, Fuller Albright first used this term in 1942. Since then, it variously has been called the “resistant ovary” or “Savage” syndrome, premature ovarian failure, hypergonadotropic hypogonadism, primary hypogonadism, and hypergonadotropic amenorrhea (1).
New epigenetic mechanism involved in leiomyoma formation Uterine leiomyomas (fibroids or myomas) are the most common benign pelvic tumors in women. They may be small or large, single or multiple, and can result in substantial distortion of the uterine surface or cavity. Although leiomyomas are benign, they commonly result in severe symptoms such as heavy, irregular, and prolonged menstrual bleeding (associated with iron-deficient anemia), dysmenorrhea, and pelvic pain and infertility, negatively affecting women’s health. Uterine fibroids have also been associated with numerous other medical disorders such as preterm labor and recurrent spontaneous abortion (1).
Is it time to broaden the scope of fertility-sparing treatments for early-stage cervical cancer? Cervical cancer is the fourth leading cause of female cancer and female mortality worldwide. Notably, screening programs, together with socioeconomic changes and advances in diagnostic and treatment algorithms have not only increased awareness but also diminished its incidence and lethality over the last decades, despite an increased risk ascribed to sexual behavioral changes over the 20th and 21st centuries (1). As a result, a non-negligible percentage of women are diagnosed at early stages and at a reproductive age, often with unfinished reproductive programs.
The time has come to reevaluate the fertilization check Embryology has evolved tremendously over the past 40 years owing to improvements in culture systems, cryopreservation, intracytoplasmic sperm injection, and the development of genetic technologies enabling the screening of embryos by means of direct karyotyping. During this time, the fertilization check is one of the few embryology procedures that has persisted relatively unchanged. As blastocyst culture is becoming commonplace, the previous inclination to monitor embryo development daily is quickly becoming a thing of the past.
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.
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.
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.
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).
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).
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.
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.
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.
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.
Thank You to Our Reviewers No journal can be successful without the support of professionals in the field who donate their time and expertise in reviewing manuscripts. Below is the list of reviewers who submitted their comments between November 1, 2019 and October 31, 2020. We would like to express our sincere gratitude to all of them.
Billing, coding, and practice management: a primer for today’s reproductive medicine professional Despite years of recognition that many physicians are woefully unprepared to face challenges regarding the business of medicine, marginal progress has been made. In this piece, we aim to provide the contemporary reproductive medicine physician with an understanding of billing, coding, and, most importantly, cost containment for a typical fertility practice. It is critical for modern practices to not forego hard-earned revenue to insurance companies or not be aware of critical rules and regulations.
How organoids from endometrium and endometriosis could help to understand the pathogenesis of endometriosis The article on methylation of HOX genes (1) in endometrium and endometriosis organoids is carefully performed and important research. Organoids, or the in vitro culture of cells as three-dimensional structures, are a rapidly developing new technology. The most important advantage of organoids is their phenotypic and genetic stability and long-lasting commitment to the tissue of origin during long-term culture (2). This characteristic was previously found only in specific immortalized monolayer cultured cell lines, which unfortunately differed from the original cells in many aspects.
Peripheral lymphocyte telomere dysfunction: a valid surrogate marker for female fertility? Telomeres are multiple short tandem DNA repeat sequences (5′-TTAGGG-3′), that cap the ends of linear chromosomes and bind a specialized telomere protein complex called shelterin to form telomere loops. The telomeres function to protect the genome from degradation, unwanted deletion, or recombination (chromosome end fusions and genomic instability) to maintain its genetic integrity. Without telomere protection, DNA damage response pathways result in cell cycle arrest, genomic instability, apoptosis, or senescence.
Glycemic status and fertility—implications for preconception care There is an increasing interest in understanding the relationship between overall health status and fertility, both in how poor health may impact fertility and in how poor fertility may affect health status later in life. Much of the focus to date has been on clinically overt disease. For example, there is a growing literature showing that time to conception is longer for women with diabetes than for women without diabetes (1). Conversely, women with a history of infertility also seem to be at greater risk of developing diabetes (2).
The need for business in reproductive medicine The business of medicine continues to be an area of growing importance, particularly in reproductive medicine. We provide a synthesis of salient concepts within the spectrum of business in medicine. The topics we review include finances and accounting; business operations as related to human resources, information technology (telemedicine), organizational governance, and practice models; insurance billing and contract negotiations; and the impact of health care policy on reproductive medicine.
The times they are a-changin’: Isn’t it time to expand the trainee curriculum? The prospect of completing formal training from medical school, to residency, to fellowship, and to entering the workforce is what drives most of us. The innate goal that is driven home by our teachers and mentors is to learn best practices and develop a skill set that allows for the provision of a specialty level of care. The hope is we all feel well prepared by the time that new role comes to fruition and have a sense of being able to function as an independent reproductive endocrinologist.
Ethanol sclerotherapy for endometriomas: ready for prime time? Nearly all reproductive health professionals have encountered the dilemma of the dreaded endometrioma, particularly for patients pursuing assisted reproductive technology (ART). For example, consider a patient with a 4-cm endometrioma that obstructs the pathway to follicular aspiration for oocyte retrieval. The clinician is then left with two options to offer the patient. One option is to proceed with egg retrieval and potentially miss aspiration of follicles resulting in lower oocyte yield. The alternative option is to proceed with laparoscopic ovarian cystectomy, which incurs the risk of decreasing ovarian reserve, as well as requiring the patient to delay ART and undergo surgery.
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