INTRODUCTION: Nexplanon (etonogestrel drug implant [EDI]) is an effective, implantable subdermal contraceptive that releases progestin over 3 years for suppression of ovulation and thickening of cervical mucus. A significant portion of EDI patients will remove their device prematurely because of bothersome episodes of frequent/prolonged bleeding. In patients with abnormal uterine bleeding, induction of a withdrawal bleed, with the goal of reducing excessive bleeding, is a common approach. There is no standard approach to treating prolonged and/or excessive bleeding with EDI in place. METHODS: This is a randomized double-blinded placebo-controlled trial of 51 patients desiring EDI for contraception. Patients received norethindrone (NTA) 5 mg or placebo daily for 1 week every 4 weeks for a total of 6 months. RESULTS: No patients in the treatment arm requested removal because of bothersome bleeding as defined by International Federation of Gynecology and Obstetrics/World Health Organization criteria. In contrast, 24% of the placebo group participants requested removal of the device at or before 6 months from placement for a variety of reasons including bothersome bleeding. 9% from the treatment group requested early removal; however, none for bothersome bleeding. 80% of the treatment group participants had a satisfactory bleeding pattern. One participant in the treatment arm complained of unsatisfactory amenorrhea. CONCLUSION: We propose a novel method to manage bothersome bleeding associated with EDI. Our data suggest that cyclic NTA is an effective method to treat bothersome bleeding in patients using etonogestrel implants for contraception and warrants further study.

Endometriosis is a reproductive enigma as few conditions in medicine are as mysterious and hard to understand. There are several potential etiologies for endometriosis, and the pathophysiology is equally diverse with a wide range of clinical presentations. Endometriosis often presents with cyclic pelvic pain and infertility, but its inflammation and dysregulation extend to multiple organ systems. Disease recognition is also poor with up to a decade or more in the delay of diagnosis, with many patients initially misdiagnosed (1Taylor H.S. Kotlyar A.M. Flores V.A. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations.Lancet. 2021; 397: 839-852Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Although surgical pathology has been traditionally the gold standard, visualization at the time of surgery of superficial or deep infiltrating lesions and endometriotic cysts or endometriomas is considered diagnostic. Likewise, infections of the pelvis, including pelvic inflammatory disease (PID) or tubal ovarian abscesses (TOA), are often misdiagnosed, overdiagnosed, and underdiagnosed with a profound impact on reproductive potential. Tubal infertility and in worst-case scenarios, hysterectomy or salpingectomy can occur when conservative therapy fails. The challenge of diagnosis and treatment is compounded when endometriosis and infection coexist because the symptoms overlap and imaging may not differentiate a TOA from an endometrioma. The presence of endometriotic fluid may also serve as a nidus for infection or an avascular incubator for bacteria protected from antibiotic therapy. Previous studies have supported the notion that an endometrioma is a risk factor for PID or TOA because it serves as a growth medium or an in vivo chocolate agar petri dish. Shats et al. (2Shats M. Bart Y. Burke Y.Z. Cohen S.B. Zolti M. Zajicek M. Endometrioma increases the risk of antibiotic treatment failure and surgical intervention in patients with pelvic inflammatory disease.Fertil Steril. 2023; 119: 1008-1015Abstract Full Text Full Text PDF Google Scholar) addressed the challenges inherent in treating women with endometriosis who develop a pelvic infection as they shed light on treatment outcomes. They retrospectively evaluated a cohort of 116 patients with known endometriosis from a university-based tertiary care center. The control group included 59 patients with endometriosis (superficial or deep infiltrating lesions) without an endometrioma. In their cohort, patients with an endometrioma and a superimposed PID were less responsive to standard antibiotic treatment and more likely to require surgical intervention. Duration of hospitalization, need for readmission, and evidence of sepsis or positive blood cultures did not increase in patients with endometriomas. A history of infertility was more common in the endometrioma group. For those of us who commonly treat infertility and worry about the potential negative impact of our treatments, it was somewhat reassuring that recent oocyte retrieval, embryo transfer, intrauterine insemination, or hysteroscopy were not associated with an increased risk of severe PID. However, the small number of patients in the subgroup with recent oocyte retrieval and the lack of information regarding whether entry into an endometrioma occurred limit any meaningful change in the dogma to avoid entering an endometrioma, when possible, during egg retrievals. Several potential confounders exist in the cohort. The patients represent a unique subset of women with endometriosis who likely failed initial treatment and were referred to a tertiary "Endometriosis Center." Although insertion of an intrauterine device carries only a very small risk of pelvic infection, the study group was less likely to have an intrauterine device in place compared with the control group. The potential for misdiagnosing an endometrioma as a TOA or pelvic abscess is also a potential confounder. The diagnosis of endometriosis was not confirmed surgically in almost half of the patients but instead relied on imaging with ultrasound or magnetic resonance imaging. The study included only hospitalized individuals; therefore, generalizability to outpatient treatment of PID is limited. Timely, accurate diagnosis and effective treatment are critical in the treatment of pelvic infections. Although endometriosis muddies the water when caring for patients with PID or a TOA, Shats et al.'s (1Taylor H.S. Kotlyar A.M. Flores V.A. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations.Lancet. 2021; 397: 839-852Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar) work raises awareness of the potential need for surgical intervention. Heightened clinical suspicion is essential to limit both short-term complications of persistent infection and the long-term burden of chronic pelvic pain and infertility. This submission has improved the care of our patients by further demystifying the enigma of endometriosis when pelvic infection is present. Endometrioma increases the risk of antibiotic treatment failure and surgical intervention in patients with pelvic inflammatory diseaseFertility and SterilityVol. 119Issue 6PreviewTo evaluate the outcome of pelvic inflammatory disease (PID) in patients with endometriosis with and without ovarian endometrioma. Full-Text PDF

Breast cancer is a leading cause of death among reproductive-age women and, understandably, a source of anxiety and fear for many. Several risk factors for this often-devastating disease have been identified, including family history, obesity, socioeconomic status, and diet. Nulliparity, both elective and because of infertility, additionally confers an increased risk. Countless publications have addressed the association between exogenous hormones and breast cancer, but the link between fertility medications and cancer is unclear. The assessment of breast cancer risk is difficult for women who seek fertility treatment in their 20s and 30s because the peak incidence of breast cancer is 3 to 4 decades later. Unfortunately, a large, randomized trial comparing fertility medications with placebo or expectant management has not been conducted. Such a trial would be costly, require long-term follow-up, and not be feasible for the simple reason that it would be unethical to withhold fertility treatment. In addition, there is a lack of large databases for women using oral and/or injectable fertility medications. Although tremendous progress has been made in short-term follow-up of women undergoing in vitro fertilization, there currently is no mandate for long-term follow-up of In vitro fertilization patients or those undergoing ovulation induction. These challenges cloud our ability to judge the true risk of breast cancer associated with fertility treatments and highlights the need for systematic reviews and meta-analysis as undertaken in this study. Beebeejaun et al. (1Beebeejaun Y. Athithan A. Copeland T.P. Kamath M.S. Sarris I. Sunkara S. Risk of breast cancer in women treated with ovarian stimulation drugs for infertility: a systematic review and meta-analysis.Fertil Steril. 2021; 116: 198-207Abstract Full Text Full Text PDF Scopus (2) Google Scholar) compared the risk of breast cancer among women using ovarian stimulation drugs (clomiphene citrate [CC] and/or gonadotropins [Gnd]). Women from the general population and those with the diagnosis of infertility who had not taken ovarian stimulation medications served as controls. Their search identified case–control and cohort studies published in English language journals from 1990 to January 2020. No randomized control trials were available. Case reports and case series were excluded. Their algorithm identified an impressive 4,148 abstracts. However, only 20 full-text citations were suitable for evaluation. Eight of the studies were retrospective, and 12 were historical prospective studies. This low number reflects the limitations of the current literature and hampers subgroup analysis. The risk of breast cancer after CC was compared with that in unexposed women in the general population in 10 studies. Women with infertility who had not taken medication served as controls in nine studies. The risk after the use of Gnd was addressed with unexposed women in the general population serving as controls in seven studies, patients with infertility served as controls in seven studies, and a mixed control group was used in 14 of the citations. Eight studies included women who took both CC and Gnd vs. unexposed infertile women and women from the general population. Finally, four studies compared women who took both CC and Gnd and unexposed women in the general population. The overlap of the comparison groups used for analysis increases the impact of any inherent bias or confounders that were not controlled for properly. The use of women from the general population, many of who have normal fertility and are parous, further compromises the data. Despite the heterogeneity within and between the studies and the potential for confounding bias, meta-analysis of all the comparison groups showed no significant increase in the risk of breast cancer. The box plots provided in Figures 1–4 in the addendum clearly display the nonsignificant odds ratios for breast cancer after CC and Gnd treatment. A major limitation of this systematic review is the failure to include ovulation induction cycles utilizing aromatase inhibitors such as letrozole. Letrozole is Food and Drug Administration approved as an adjunction for breast cancer treatment and would potentially limit the stimulation of breast tissue compared with CC and Gnd. The Reproductive Medicine Network trial, Pregnancy in Polycystic Ovarian Syndrome II, demonstrated that letrozole is more successful at inducing ovulation with a higher pregnancy rate compared with CC in women with PCOS. In addition, women with polycystic ovarian syndrome may be at increased risk of breast cancer because of high incidence of obesity and the frequent presence of metabolic confounders (2Legro R.S. Brzyski R.G. Diamond M.P. Coutifaris C. Schlaff W.D. Casson P. et al.Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.N Engl J Med. 2014; 371: 119-129Crossref PubMed Scopus (291) Google Scholar). In addition, investigators noted that the data included in their analysis did not allow them to control for several confounders, especially obesity. Only 14 of the 20 studies attempted to adjust for any of the confounders known to impact breast cancer risk. The supplementary figures provided by the investigators are helpful in visualizing the high risk of bias and the significant impact of confounders in their submission. In addition, the investigators recognized the advantage of prospective studies and the greater risk of bias in retrospective data sets. However, a sensitivity analysis involving only the prospective studies reached the same conclusion. One additional challenge for case and cohort studies is the time course of the disease in question. Although the average follow-up duration of the studies included in the analysis was 27.1 years, two studies did not report the follow-up duration, and six of the studies had follow-up intervals of <12 years. A generation of women believes that the use of all hormones increases the risk of breast cancer. This common misperception is due in part to the results of the Women's Health Initiative and the subsequent alarmist media reports. Follow-up reports regarding the use of estrogen alone and the impact of age at initiation were largely ignored. In addition, many primary care and women's healthcare providers are under the impression that all hormones, including oral contraceptives, hormone replacement therapy, and fertility medication, increase the risk of breast cancer. This misconception remains challenging for patients and providers as there are undoubtedly women who would benefit from oral contraceptives, hormone replacement therapy, or fertility treatments who choose not to seek treatment because of an overestimation of the risk involved. The investigators provide a compelling argument that the use of CC and Gnd does not increase one's risk of breast cancer, but the limited data available for analysis does not clearly prove that no risk exists. The challenge for researchers and clinicians alike is to continue to improve the quality of the research while educating our patients and the public regarding the true risks inherent in the fertility treatment. A large multinational prospective cohort with lifelong follow-up is needed to assess the impact of fertility treatments on breast cancer risk. Beebeejaun et al. should be commended for their noteworthy effort to address this significant issue. Although the cloud of breast cancer risk hangs over all women, this meta-analysis and systematic review offers some reassurance that the pursuit of motherhood for those who suffer from infertility does not increase the risk of breast cancer. Risk of breast cancer in women treated with ovarian stimulation drugs for infertility: a systematic review and meta-analysisFertility and SterilityVol. 116Issue 1PreviewTo evaluate the evidence addressing the association between the use of ovarian stimulation drugs and the risk of breast cancer. Full-Text PDF

A 1998 New York Times article suggested that the term transparency had ascended to a moral height that surpasses honesty, sincerity, and authenticity as a requirement of government, business, and medicine (1Boxer S. Transparent enough to hide behind. New York Times December 19, 1998, p. D7.Google Scholar). The demand for transparency in medical care is widespread and, as a corollary, medical research. Despite this focus, many would argue transparency in medical research is akin to peering through frosted glass. In this issue, Kemper et al. (2Kemper J.M. Rolnik D.L. Mol B.W.J. Ioannidis J.P.A. Reproducible research practices and transparency in reproductive endocrinology and infertility articles.Fertil Steril. 2020; 114: 1320-1327Abstract Full Text Full Text PDF Scopus (2) Google Scholar) analyzed the reproductive endocrine and infertility (REI) literature to examine transparency and reproducibility. Full-text original articles from five REI-specific journals including Fertility & Sterility from 2013 (n = 98) and 2018 (n = 90) were compared with REI articles published in five high-impact journals including New England Journal of Medicine (NEJM) and Journal of the American Medical Association (JAMA). The timeframe (2013–2018) for the review of the comparison group was arbitrarily chosen. Each article was assessed for study type, sample size, trial registration, protocol and raw data availability, funding and conflict of interest declarations, and citation counts. Inclusion in subsequent systematic reviews and/or meta-analysis and novelty versus replication of the work also were noted. The majority of studies in both groups were not registered prospectively and did not include protocols. Both were more likely to be found in high-impact journal articles. Data sharing was not readily available in either group, but the authors noted that in the last year the NEJM and JAMA have started requiring data-sharing statements. Fertility & Sterility also encourages the practice now. High-impact journals are cited more frequently in subsequent research article, as would be expected given the wider appeal and larger readership. By definition, higher-impact journals have more citations because the impact score is determined by the number of articles cited. An encouraging finding was that the vast majority of articles contained a conflict of interest statement even before most journals required its inclusion. A greater percentage of articles in high-impact general journals also claimed to be novel; it is rare for a submission to clearly state that it is replicating prior studies. However, one cannot help but wonder if a novel claim positively biases reviewers and editors, whereas an upfront statement of replication in a submission could be the kiss of death. It is important to note that “novelty” was determined using authors’ claims, not in an independent evaluation. Novelty is often treated as the gold standard for research, but it may be overrated. Many studies warrant further investigation and confirmation. Despite this article’s conclusion that high-impact journals had greater transparency, other authors have reported that efforts to reproduce studies from the highest-impact journals often fail, leading some authors to refer to a reproducibility crisis in medical research. Complete transparency in research is a lofty goal but the openness required to achieve it may be counterintuitive in today’s research climate. Competition for limited research funding is intense. Individual researchers are judged by number and quality of publications and success in obtaining grants. Likewise, academic leaders are benchmarked by their research revenue because margins from clinical dollars are unable to support research. Institutions of higher learning also tout their intramural funding rank with great pride. All levels in the multi-billion dollar research enterprise seemingly are incentivized to compete and competition often brings secrecy and hording of innovation and thought. On the other side of the equation, journals take great pride in their impact factor, sending out mass e-mails and press releases when it moves by mere percentage points to increase scientific standing and advertising dollars. The proliferation of for-profit journals adds additional options for researchers to publish their work but may promote volume over quality and data mining over innovation. It may be argued that these pressures are remnants from a bygone era, and we have entered a more enlightened time where sharing and community take precedence. Although junior researchers strongly support the notion of high standards and transparency in research, they also overwhelmingly feel that “other” investigators seek an advantage by cutting corners and limiting access to their research (3National Academies of Sciences, Engineering, and Medicine 2020. Enhancing scientific reproducibility in biomedical research through transparent reporting: proceedings of a workshop. Washington, DC: The National Academies Press; 2020. https://doi.org/10.17226/25627.Google Scholar). On the bright side, research networks have become the norm with the realization that a team approach maximizes financial resources, stimulates innovation, and enhances the impact of research findings with economies of scale. Many individuals and departments also are furthering their research cache with these strategic partnerships at the local, regional, and national level as well as within specific medical societies. The reproductive medicine network is a great example of this approach. Kemper et al. (2Kemper J.M. Rolnik D.L. Mol B.W.J. Ioannidis J.P.A. Reproducible research practices and transparency in reproductive endocrinology and infertility articles.Fertil Steril. 2020; 114: 1320-1327Abstract Full Text Full Text PDF Scopus (2) Google Scholar) suggest that greater attention is being focused on transparency in meta-research, the study of research studies. The National Academy of Sciences convened a consensus workshop in September 2019 to identify biases inherent in research by focusing on transparency and reproducibility in biomedical research (3National Academies of Sciences, Engineering, and Medicine 2020. Enhancing scientific reproducibility in biomedical research through transparent reporting: proceedings of a workshop. Washington, DC: The National Academies Press; 2020. https://doi.org/10.17226/25627.Google Scholar). Transparency was defined as the disclosure of data, materials analysis, and methodology with a goal of standardizing guidelines across journals and funding agencies. The workshop participants also cited a growing emphasis on meta-research specifically addressing a study’s methods, reporting, reproducibility, evaluation, and incentives. The ultimate goal of this type of research is to ensure opportunities for expansion of knowledge and innovations while identifying any threats to validity and scientific integrity. Unfortunately, this group also found that less than half of the studies they reviewed were transparent and provided the “full array” of data and details necessary to reproduce the research. The National Academy of Sciences workshop also made an interesting assertion that replication is not always required. Confirmation of research findings happens routinely as researchers build upon prior work. These replications are not reported. Some participants argue that studies should be replicated if the results are controversial or unexpected or if the study is to be used in making decisions of consequence. The last assertion is noteworthy because all decisions in health care have consequences. In our field, patients and families will benefit or suffer based on the veracity of reproductive research. Despite the potential benefits of confirming results, one can argue that research should focus less on reproducibility and more on transparency. On a practical level, transparency may be best accomplished with preregistration of research protocols and availability of data sharing. The challenge is to incentivize researchers, improve funding sources, and stipulate that publications reflect a commitment to transparency (4Ioannidis J.P.A. Why research on research matters.PLOS Biol. 2018; 16e2005468Crossref PubMed Scopus (104) Google Scholar). Kemper et al. (2Kemper J.M. Rolnik D.L. Mol B.W.J. Ioannidis J.P.A. Reproducible research practices and transparency in reproductive endocrinology and infertility articles.Fertil Steril. 2020; 114: 1320-1327Abstract Full Text Full Text PDF Scopus (2) Google Scholar) highlight the improvements and limitations in reproductive research. Rather than a critique, theirs is a rallying cry for further improvements in the conduct and reporting of research. Reproductive medicine should demand transparent reproducible research that is on equal footing or exceeds other areas of biomedical research. Fertility & Sterility should lead the way by requiring data-sharing statements where appropriate and providing full support of measures to increase transparency. The pursuit of transparency is by no means a modern concept. Transparency of thought appeared in Greek Tragedies and was a rallying cry during the French Revolution, where lack of transparency might result in beheading. Fortunately, a trip to the Guillotine does not await researchers who choose to remain behind frosted glass. Our field and future generations deserve nothing less than quality research that improves the practice of reproductive medicine and patient outcomes. Reproducible research practices and transparency in reproductive endocrinology and infertility articlesFertility and SterilityVol. 114Issue 6PreviewTo analyse the published literature in reproductive endocrinology and infertility (REI) to examine the transparency and the use of reproducible research practices of the scientific literature and to identify possible avenues for improvement. Full-Text PDF

Polycystic ovary syndrome (PCOS) has been described as the most common endocrine disorder affecting reproductive age women. PCOS is often associated with metabolic dysfunction, obesity, glucose intolerance with hyperinsulinemia, lipid abnormalities. and hypertension. Women with PCOS also suffer higher rates of cardiovascular (CV) disease, peripheral vascular disease, stroke, diabetes, sleep apnea, non-alcoholic fatty liver disease, and breast and uterine cancer. However, rather than a strict cause and effect relationship, many have argued that these conditions are independent or related to a specific feature such as obesity or glucose intolerance in women who also have PCOS and are not a requisite part of the syndrome (1Legro R.S. Evaluation and treatment of polycystic ovary syndrome.in: De Groot L.J. Chrousos G. Dungan K. Endotext. MDText.com, Inc., Massachusetts2017Google Scholar). The lack of a clear, consistent association between PCOS and metabolic dysfunction limits the value of routine metabolic screening of all women with PCOS. Likewise, the wide range of clinical presentations of PCOS, the cost of comprehensive metabolic screening, and the low potential for meaningful results that would alter treatment also argue against universal PCOS metabolic screening. Identification of specific risk factors or phenotypes that would benefit from screening and early interventions or lifestyle modification would aid clinicians and optimize care of these women. Marchesan and colleagues (2Marchesan L.B. Spritzer P.M. ACC/AHA 2017 definition of high blood pressure: implications for women with polycystic ovarian syndrome.Fertil Steril. 2019; 111: 579-587Scopus (21) Google Scholar) suggest that hypertension may be an important clinical marker for metabolic dysfunction in women with PCOS. Their cross-sectional study demonstrated an association between hypertension and higher risk of metabolic dysfunction when compared with normotensive women with PCOS. Although the link between hypertension and metabolic dysfunction is not a novel concept, they expanded our insight into this association by use of the latest American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Hypertension was defined by the 2017 ACC/AHA criteria: systolic blood pressure >130 mmHg and diastolic blood pressure >80 mmHg. Although the authors used the commonly employed Rotterdam criteria for the diagnosis of PCOS, they also divided the study subjects into classical PCOS with ovulatory dysfunction, androgen excess with or without PCO morphology and ovulatory PCOS with androgen excess and PCO morphology. Sixty-five percent of the women with PCOS in this study had hypertension as defined by the latest ACC/AHA criteria while 27% had hypertension using the traditional thresholds of systolic blood pressure >140 mmHg and diastolic blood pressure >90 mmHg. Not surprisingly, study subjects with “classic” PCOS were heavier, had higher testosterone, cholesterol and triglyceride levels, reduced glucose tolerance, increased insulin resistance and increased blood pressure when compared to women with ovulatory PCOS. There was no significant difference in the incidence of hypertension or in most of the endocrine and metabolic parameters when women with ovulatory PCOS were compared to the controls. Metabolic variables, except for fasting glucose and high-density lipoproteins, were higher in the classic PCOS group when compared with the ovulatory PCOS and controls even when adjusted for age and body mass index. This finding highlights the wide spectrum of hormonal and metabolic profiles seen with PCOS. Although many authors have argued that androgen excess is the key to ascertaining metabolic risk, androgen levels were not an independent risk factor for metabolic dysfunction and testosterone levels did not differ based on blood pressure readings in this study. However, body mass index >25 kg/m2 was a risk factor for hypertension. SAH was also associated with higher HOMA-IR and insulin levels in all the PCOS study subjects supporting the notion demonstrated by other researchers that hyperinsulinemia may influence blood pressure. Hyperinsulinemia also plays a pathogenic role in many cases of PCOS and the metabolic syndrome (3Ehrmann D.A. Liljenquisy D.R. Kasza K. Azziz R. Legro R.S. Ghazzi M.N. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome.J Clin Endocrinol Metab. 2006; 91: 48-53Crossref PubMed Scopus (525) Google Scholar). Rather than being isolated risk factors for subsequent disease, many of the features that coexist with PCOS (obesity, hyperinsulinemia and hypertension) likely form a complex and interrelated web that predicts poor health. It is important to note that the diagnosis of SAH are based on the 2017 ACC/AHA guidelines (4Whelton P.K. Carey R.M. Aronow W.S. Casey D.E. Collins K.J. Himmelfarb C.D. et al.2017 ACC/AHA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines.J Am Coll Cardiol. 2018; 71: 127-248Crossref PubMed Scopus (2615) Google Scholar) and the Systolic Blood Pressure Intervention Trial (Sprint) (5SPRINT Research GroupA randomized trial of intensive versus standard blood-pressure control.N Engl J Med. 2015; 373: 2103-2116Crossref PubMed Scopus (3932) Google Scholar). The SPRINT trial demonstrated that aggressive control of blood pressure (systolic blood pressure <120 mmHg and diastolic blood pressure <80 mmHg) significantly reduced myocardial infarction, acute coronary syndrome, stroke, heart failure and death from CV causes. The trial was stopped early, and the ACC/AHA guidelines updated due to the dramatic impact of tighter blood pressure control. However, application of the results to women with PCOS is limited at best as 65% of the study participants were men, many were over the age of 75 and all had at least one significant CV risk factor (existing CV disease, chronic kidney disease and 10-year CV risk of >15% on the Framingham risk assessment). It is also noteworthy that individuals with diabetes mellitus were excluded from the SPRINT trial. Despite the lack of generalizability of the SPRINT trial and limited data to support adopting the 2017 ACC/AHA guidelines in women with PCOS, the authors should be commended for their contribution to recognition of early blood pressure abnormalities as a risk factor for metabolic dysfunction and their hypothesis warrants further study. Identification of those women at risk early in their clinical care holds promise for primary prevention and interruption of the metabolic dysfunction. Although most reproductive endocrinology and infertility specialists are aware of the potential negative metabolic sequalae and the long-term morbidity associated with PCOS, ovulatory dysfunction and fertility are often the focus of clinical care. As reproductive endocrinologists it is our responsibility to look beyond assisted reproductive technologies and help our patients escape the PCOS web of reproductive and metabolic dysfunction to achieve not only pregnancy but lifelong health and wellness. ACC/AHA 2017 definition of high blood pressure: implications for women with polycystic ovary syndromeFertility and SterilityVol. 111Issue 3PreviewTo assess the association of insulin resistance markers, body mass index (BMI), age, and androgen levels with systemic arterial hypertension (SAH) defined according to 2017 American College of Cardiology/American Heart Association (ACC/AHA) criteria in polycystic ovary syndrome (PCOS); and to determine the risk of metabolic abnormalities in the presence of SAH defined by both the 2017 ACC/AHA and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) criteria in women with PCOS. Full-Text PDF

Few conditions in reproductive medicine have greater potential to destroy the hope and dreams of parenthood than premature ovarian failure or insufficiency. Patients often view this diagnosis as an insurmountable obstacle on their path to achieving pregnancy. Even when they are counseled regarding the potential for pregnancy, they report a hopeless loss of control. Previous authors have stressed the inaccuracy of the term ovarian "failure" describing it as medically misleading and even offensive and psychologically hurtful, with patients experiencing feelings akin to learning about the death of a family member when given this diagnosis. The term premature ovarian insufficiency (POI) is now preferred and reflects the possibility of future ovarian function (1Nelson L.M. Covington S.N. Rebar R.W. An update: spontaneous premature ovarian failure is not an early menopause.Fertil Steril. 2005; 83: 1327-1332Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). In many cases of POI, the etiology is unknown or may represent an autoimmune process. Conversely, genetic abnormalities or exposure to gonadotoxic therapies including chemotherapy and radiation clearly result in ovarian dysfunction. Regardless of the terminology or cause, clinicians often struggle with the lack of proven options to permanently restore ovarian function and truly offer the promise of a successful birth of a genetically related offspring. The article by Herraiz and colleagues (2Herraiz S. Buigues B. Díaz-García C. Romeu M. Martinez S. Gómez-Seguí I. et al.Fertility rescue and ovarian follicle growth promotion by bone marrow stem cells.Fertil Steril. 2018; 109: 908-918Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar) raises the possibility that hope is on the horizon for ovarian rejuvenation with mesenchymal stem cell (MSC) technology. The murine model has been especially productive in preliminary work on the ability of MSCs to contribute to differentiation into functional gametes or contribute to gonadal rejuvenation. Likewise, bone marrow derived stem cells (BMDSCs) have shown early promise utilized immunodeficient female mice with chemotherapy-induced ovarian damage to investigate the possibility that human BMDSC infusion could promote ovarian angiogenesis and improve follicular development (2Herraiz S. Buigues B. Díaz-García C. Romeu M. Martinez S. Gómez-Seguí I. et al.Fertility rescue and ovarian follicle growth promotion by bone marrow stem cells.Fertil Steril. 2018; 109: 908-918Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Infusion of standard peripheral blood mononuclear cells were used as controls to determine if in fact the regenerative properties were due to the bone marrow derived cells and not circulating blood cells. A second phase of their experiment involved ovariectomized animals who were xenografted with human ovarian cortex from patients with POI and treated with infusion of BMDSCs. As one would expect, the investigators demonstrated that animals administered a reduced dose of chemotherapy were more likely to retain ovarian function, highlighting the fact that spontaneous return of fertility is not uncommon. In animals with ovarian failure, BMDSC infusion resulted in an increase in ovarian vascularization and weight, reduction in apoptosis and increase in cell proliferation with greater primordial, antral and pre-ovulatory follicle number compared to controls. Likewise, the animals receiving BMDSC infusion had a return of both proestruse and estrus phases, an increase in metaphase II oocytes and increase in fertilization rate. Ultimately, BMDSC treated animals achieved up to three consecutive pregnancies. None of the animals in the control group who received the standard chemotherapy dose demonstrated ovarian rejuvenation or function and none achieved a pregnancy. A crucial element of their experiments was the clear demonstration that the labeled BMDSC infused through the tail clearly tracked or homed to the damaged ovaries as well as the human xenografts. The authors also demonstrated that BMDSC infusion had a regenerative effect on the human ovarian cortex xenografts. BMDSCs resulted in increased cellular proliferation, increased follicular density, improved vascularization and an increase in estradiol secretion. The authors concluded that human BMDSCs infusion promoted ovarian function and resulted in the birth of healthy pups from mice with chemotherapy induced infertility. Although somewhat beyond the scope of their investigation, they also speculated that autologous BMDSC therapies could be an alternative to improve follicular development in aging women and patients with POI not associated with chemotherapy or radiation. Almost two decades have elapsed since the concept that pluripotent stem cells could differentiate into functional gametes was introduced. In the intervening years, primordial germ cells, very small embryonic-like stem cells (VSELs), multi-lineage differentiating stress enduring cells and ovarian stem cells (OSCs), to name a few, have been associated with the recruitment and stimulation or conversion into functional gametes. Two recent systematic reviews by Fazeli et al. (3Fazeli Z. Abedindo A. Omrani M.D. Ghaderian S.M.H. Mesenchymal stem cells (MSCs) therapy for recovery of fertility: a systematic review.Stem Cell Rev and Rep. 2018; 14: 1Crossref PubMed Scopus (67) Google Scholar) and Bhartiya et al. (4Bhartiya D. Anand S. Patel H. Parte S. Making gametes from alternate sources of stem cells: past, present and future.Reprod Biol Endocrinol. 2017; 15: 1-14Crossref PubMed Scopus (31) Google Scholar) have highlighted the tremendous advances in our understanding of the pleuripotency of MSCs relative to germ cells. In addition, it is clear that both paracrine and autocrine signals in the ovarian microenvironment or niche are required for normal function. Both gonadotoxic therapies and aging appear to compromise the ovarian niche. Although it is very unlikely that the ovarian senescence seen with aging mirrors ovarian damage from gonadotoxins, chemotherapy-induced ovarian damage provides an excellent animal model for investigation. The ability of MSCs to migrate or "home" to damaged gonads is a crucial tenet of this theory and is well supported by the current literature. However, the questions remain whether the stem cells differentiate into gametes upon arrival, induce regeneration of nonfunctioning ovaries through paracrine signaling, or do both mechanisms play a role. Numerous potential extragonadal sources of gametes including bone marrow and somatic organs have been reported. It is not surprising that bone marrow may contain primordial germ cells or other pluripotent stem cells that are capable of conversion to gametes since there is a strong developmental link between the hematopoietic system and reproductive system. Bone marrow expresses numerous germ cell markers and BMDSCs contain both pituitary and sex hormone receptors. Multi-lineage differentiating stress enduring cells are also of particular interest as they migrate into damaged tissue via the bloodstream and differentiate into gamete-like cells. Despite the clear suggestion that extragonadal stem cells possess the ability to differentiate, one can make a strong argument that MSCs have a greater impact on ovarian function through residual stem cells in the ovary (VSELs and OSCs) via paracrine communication. Numerous combinations of growth factors and signaling molecules produced by MCSs are involved in this process. This concept is supported by several in vitro studies and the fact that MSC's microvesicles and the signaling molecules they contain have a beneficial effect on ovarian function via VSELs. VSELs have been described as a back-up population of ovarian stem cells with the potential to undergo conversion to functional gametes. Transplanting autologous MSCs into nonfunctioning ovaries results in new follicular development from endogenous VSELs. Both VSELs and OSCs also appear to undergo neo-oogenesis and follicular assembly as a result of extragonadal stem cell arrival in the ovary. VSELs are a particularly compelling mechanism for ovarian rejuvenation because they are present in the adult ovary, express receptors for follicle-stimulating hormone and appear to be more resistant to gonadotoxic therapy because of their low metabolic rate. VSELs have been shown to survive chemotherapy in mouse ovaries and rebound with follicle-stimulating hormone stimulation. It is interesting to note that these pluripotent cells have also been observed in ovaries from postmenopausal women as well as those with POI. However, there are conflicting results on the ability of stem cells to differentiate into gamete-like cells, further supporting the notion that paracrine signaling is of paramount importance. Potential problems have also been reported with epigenetic changes and abnormal meiosis in the resulting cells. Previous experience has also warned us of the potential for tumor formation when utilizing stem cell technology. There are also ethical concerns with the use of pleuripotent cells to create gametes and offspring. Although the exact mechanism is a matter of debate, the biologic plausibility that stem cells can restore ovarian function and fertility potential is without question. Numerous publications have demonstrated successful differentiation of stem cells to gamete-like cells in vitro. In addition, in vivo murine, rat and rabbit models have expanded these findings with the production of competent oocytes and viable offspring following MSC therapy. Investigation of this technology's ability to restore ovarian function in humans clearly holds promise. If proven to rejuvenate ovaries following chemotherapy and radiation, these therapies may be expanded to all cases of POI. Eventually, one cannot help but wonder if cases of diminished ovarian reserve (low egg number or quality) or unexplained infertility may be treated with mesenchymal stem cell technology. The penultimate application of these techniques may be in fighting the ovarian senescence seen with aging. The science of ovarian rejuvenation with stem cell technology is rapidly expanding. Dr. Herraiz and colleagues (2Herraiz S. Buigues B. Díaz-García C. Romeu M. Martinez S. Gómez-Seguí I. et al.Fertility rescue and ovarian follicle growth promotion by bone marrow stem cells.Fertil Steril. 2018; 109: 908-918Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar) have contributed greatly to the growing body of literature in this arena. Their well-executed proof of concept offers those who suffer from POI a glimmer of hope, but the routine clinical application of these techniques remains on the horizon, albeit a not too distant one. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusionFertility and SterilityVol. 109Issue 5PreviewTo assess if infusion of human bone marrow–derived stem cells (BMDSCs) could promote follicle development in patients with impaired ovarian functions. Full-Text PDF

STUDY QUESTION Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? SUMMARY ANSWER AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. WHAT IS KNOWN ALREADY Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. STUDY DESIGN, SIZE, DURATION A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. MAIN RESULTS AND THE ROLE OF CHANCE Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). LIMITATIONS, REASONS FOR CAUTION Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. WIDER IMPLICATIONS OF THE FINDINGS Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. STUDY FUNDING/COMPETING INTEREST(S) Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. TRIAL REGISTRATION NUMBER Clinical Trials.gov number: NCT01044862.

BACKGROUND: While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed.OBJECTIVE: The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility.STUDY DESIGN: A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale.RESULTS: Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility.CONCLUSION: Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function.

The objective was to prospectively characterize dynamic pelvic 3-Tesla magnetic resonance imaging (dp3T MRI) findings in nulligravida women and characterize changes 6 months after delivery in the same woman.

Prostaglandins are formed by enzymatic and non-enzymatic mechanisms. They have been detected in human ovarian follicular fluid (HFF), a medium rich in growth factors and nutrients important for oocyte growth and fertility. However, the comprehensive identification of HFF prostaglandins has not been addressed. Here we use hybrid triple quadrupole time-of-flight and triple quadrupole mass spectrometers to comprehensively analyze prostaglandins in HFF. We identified PGE1, PGE2, PGF2α, and other prostaglandins synthesized via prostaglandin-endoperoxide synthase (i.e. Cox) cascades. We also identified specific PGF2α isomers (F2-isoprostanes) and PGF3α analogs whose structures are inconsistent with Cox-dependent formation. A prospective cohort pilot study of infertility patient subtypes revealed two potential associations. F2-isoprostanes are decreased in the diminished ovarian reserve subtype and elevated PGF2α may be associated with decreased live birth. Other than PGF2α, only body mass index >25kg/m2 correlated with poor in vitro fertilization outcome. Our studies suggest that HFF contains prostaglandins formed from at least two mechanisms, which may correlate with distinct clinical parameters.

Context: In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown.Objective: We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS.Design, Setting, and Participants: This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS.Intervention: We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142).Main Outcome Measures: Live birth, pregnancy loss, and ovulation were measured.Results: In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45%[67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P = .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01).Conclusions: These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.

Objective: To summarize the available evidence for the efficacy of various treatments for unexplained infertility.Design: Systematic review.Setting: Not applicable.Patient(s): Patients aged 18-40 years with unexplained infertility.Intervention(s): Clomiphene citrate, letrozole, timed intercourse, IUI, gonadotropins, IVF, and IVF-intracytoplasmic sperm injection.Main Outcome Measure(s): Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate.Result(s): Thirteen studies with a total of 3,081 patients were identified by systematic search and met inclusion criteria. The available literature demonstrates that expectant management may be comparable to treatment with clomiphene and timed intercourse or IUI. Clomiphene may be more effective than letrozole, and treatment with gonadotropins seems more effective, albeit with significantly higher risk of multiple gestations than either oral agent. On the basis of current data, IVF, with or without intracytoplasmic sperm injection, is no more effective than gonadotropins with IUI for unexplained infertility.Conclusion(s): Adequately powered, randomized controlled trials that compare all of the available treatments for unexplained infertility are needed. Until such data are available, clinicians should individualize the management of unexplained infertility with appropriate counseling regarding the empiric nature of current treatment options including IVF. (Feral Steril' 2016;105:1566-74. (C) 2016 by American Society for Reproductive Medicine.)

Before initiating ovulation induction, it is important to evaluate the underlying cause of a patient's anovulation and to make lifestyle modifications or treat underlying medical conditions, as appropriate. Here, ovulation induction agents are discussed with attention to their pharmacology, indications for use, therapy regimens, and efficacy. Adjuvant therapies and appropriate monitoring are also reviewed.

Objective To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. Design Randomized, prospective clinical trial. Setting Multicenter university-based clinical practices. Patient(s) A total of 900 couples with unexplained infertility. Intervention(s) Collection of baseline demographics, blood samples, and ultrasonographic assessments. Main Outcome Measure(s) Demographic, laboratory, imaging, and survey characteristics. Result(s) Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 ± 4.4 years and infertility duration was 34.7 ± 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimüllerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. Conclusion(s) The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimüllerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. Clinical Trial Registration Number NCT 01044862.

BACKGROUND:The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates.METHODS:We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies.RESULTS:After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications.CONCLUSIONS:In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).

Background Intramural leiomyomas have been long debated as a potential cause of infertility and pregnancy loss. Findings Previous research has linked intramural fibroids to defective implantation, as well as to abnormal peristaltic events of the uterine smooth muscle. Previous reports describe the effects of intramural fibroids on normal human fertility and early pregnancy loss, specifically in regards to implantation failure. Conclusion A thorough understanding of prior research may direct new research focus, leading to better understanding of leiomyoma-associated infertility.