Objective: To identify the genes presenting different expression in uterine leiomyomas after goserelin treatment. Design: Retrospective analyses of tissue obtained in a prospective clinical study. Setting: School of Medicine of the University of Sao Paulo. Patient(s): 30 nulliparous black women aged 20 to 45 years with symptoms of uterine leiomyoma, uterine volume over 300 mL, and surgical indications for myomectomy. Intervention(s): Fifteen patients were given a monthly dose of 3.6 mg of goserelin over 3 months before surgery (group A), and 15 patients underwent surgery without any previous treatment (group B). Five random samples from each group were analyzed using the microarray technique with the Affymetrix platform (GeneChip Rat Genome 230 2.0 Array). Main Outcome Measure(s): Quantification of transcript expression levels of uterine fibroids in patients treated or not treated with goserelin. Result(s): Of the total of 47,000 sequences that were analyzed, representing approximately 38,500 human genes already characterized, we found a differential expression of 174 genes. Of these, 70 were up-regulated (33 genes with known function) and 104 were down-regulated (65 genes with known function) in samples from group A (treated) when compared with group B (nontreated). Conclusion(s): The genic expression of uterine leiomyomas changes in women who have had goserelin treatment when compared with nontreated patients. (Fertil Steril (R) 2010; 94: 1072-7. (C) 2010 by American Society for Reproductive Medicine.); Universidade de São Paulo - FMUSP
The discovery of small noncoding RNA, including P-element-induced wimpy testis-interacting RNA, small interfering RNA, and microRNA, has energized research in reproductive medicine. In the two decades since the identification of small RNA, first in Caenorhabditis elegans and then in other animals, scientists in many disciplines have made significant progress in elucidating their biology. A powerful battery of tools, including knockout mice and small RNA mimics and antagonists, has facilitated investigation into the functional roles and therapeutic potential of these small RNA pathways. Current data indicate that small RNA play significant roles in normal development and physiology and pathological conditions of the reproductive tracts of females and males. Biologically plausible mRNA targets for these microRNA are aggressively being discovered. The next phase of research will focus on elucidating the clinical utility of small RNA-selective agonists and antagonists.
The safety of human exposure to an ever-increasing number and diversity of electromagnetic field (EMF) sources both at work and at home has become a public health issue. To date, many in vivo and in vitro studies have revealed that EMF exposure can alter cellular homeostasis, endocrine function, reproductive function, and fetal development in animal systems. Reproductive parameters reported to be altered by EMF exposure include male germ cell death, the estrous cycle, reproductive endocrine hormones, reproductive organ weights, sperm motility, early embryonic development, and pregnancy success. At the cellular level, an increase in free radicals and [Ca2+]i may mediate the effect of EMFs and lead to cell growth inhibition, protein misfolding, and DNA breaks. The effect of EMF exposure on reproductive function differs according to frequency and wave, strength (energy), and duration of exposure. In the present review, the effects of EMFs on reproductive function are summarized according to the types of EMF, wave type, strength, and duration of exposure at cellular and organism levels.
A biomarker can be used for early diagnosis of a disease, identification of individuals for disease prevention, as a potential drug target, or as a potential marker for a drug response. A biomarker may also limit the use of drug (and therefore costs) to the population of patients where the drug will be safe and efficacious. A biomarker in reproduction could be used to improve assessment of exposure, identify subgroups susceptible to treatment, predict outcome and/or differentiate subgroups with potentially different etiologies of disease. Despite many potential uses there is low participation in reproductive biology to develop molecular biomarkers which may be directly related to the low number of new molecular entities entering clinical trials. As the number of candidate markers in reproductive medicine is increasing, it is important to understand the pathway of development from discovery to clinical utility and recognize that the vast majority of potential markers will not be clinically useful due to a variety of pitfalls. Extensive testing, validation and modification needs to be performed before a biomarker is demonstrated to have clinical utility. New opportunities and partnerships exist and should hasten the development of biomarkers in reproduction. As more biomarkers are moved into practice...
Reproductive medicine laws in Germany currently mean that the relationship status of prospective
parents is taken into consideration in decisions on whether their application for assisted
reproduction is approved or rejected. In the light of new forms of shared parenthood, we should
ask ourselves whether the current regulations are still an appropriate way of guaranteeing the
best for the child. Current medical practices and their legal basis will be illustrated using
the examples of sperm, egg and embryo donation. From an ethical perspective, the question at
stake is to what extent an “Ethics of Parenthood” can make it possible to act responsibly with
regard to the changes occurring in forms of shared parenthood. Such an ethics is aimed at
supporting parents in realising the reproductive autonomy guaranteed in the German Constitution
through social and ethical aspects of the child–parent relationship.
Health disparities exist in reproductive medicine as discussed in detail in the subsequent articles of this issue; however, in most cases, the exact cause of these differences is unknown. Some of these disparities can be linked to environmental exposures such as alcohol and other hazardous toxic exposures (polycarbonate, pesticides, nicotine) in adults. In addition, low socioeconomic status, behavioral risk factors, and lack of education have been linked to poor obstetric and reproductive outcomes in minority groups. Aside from these various environmental exposures later in life, there is evidence that adverse events in utero could contribute to poor reproductive outcome in specific minority groups. We will focus on the developmental origins of health and disease as a possible causal mechanism for health disparities in reproductive diseases, as this perspective may suggest tractable solutions of how to address and eliminate these health disparities.
Racial and ethnic health disparities in reproductive medicine exist across the life span and are costly and burdensome to our healthcare system. Reduction and ultimate elimination of health disparities is a priority of the National Institutes of Health who requires reporting of race and ethnicity for all clinical research it supports. Given the increasing rates of admixture in our population, the definition and subsequent genetic significance of self-reported race and ethnicity used in health disparity research is not straightforward. Some groups have advocated using self-reported ancestry or carefully selected single-nucleotide polymorphisms, also known as ancestry informative markers, to sort individuals into populations. Despite the limitations in our current definitions of race and ethnicity in research, there are several clear examples of health inequalities in reproductive medicine extending from puberty and infertility to obstetric outcomes. We acknowledge that socioeconomic status, education, insurance status, and overall access to care likely contribute to the differences, but these factors do not fully explain the disparities. Epigenetics may provide the biologic link between these environmental factors and the transgenerational disparities that are observed. We propose an integrated view of health disparities across the life span and generations focusing on the metabolic aspects of fetal programming and the effects of environmental exposures. Interventions aimed at improving nutrition and minimizing adverse environmental exposures may act synergistically to reverse the effects of these epigenetic marks and improve the outcome of our future generations.
Since 2006, several laboratories have proved that somatic cells can be reprogramed into induced pluripotent stem cells (iPSCs). iPSCs have enormous potential in stem cell biology as they can give rise to numerous cell lineages, including the three germ layers. In this review, we discuss past and recent advances in human iPSCs used for modeling diseases in vitro, screening drugs to test new treatments, and autologous cell and tissue regenerative therapies, with a special focus on reproductive medicine applications. While this latter field of research is still in its infancy, it holds great promise for investigating germ cell development and studying the genetic and physiopathological mechanisms of infertility. A major cause of infertility is the absence of germ cells in the testes, mainly due to genetic background or as a consequence of gonadotoxic treatments. For these patients, no effective fertility restoration strategy has so far been identified. The derivation of germ cells from iPSCs represents an alternative source of stem cells able to differentiate into spermatozoa. Lessons learned from animal models as well as studies on human iPSCs for reproductive purposes are reviewed.
Systematic reviews and accompanying meta-analyses are the cornerstones of evidence-based medicine. Systematic reviews summarize clinical evidence; meta-analyses provide summary estimates of the treatment effect or the diagnostic test accuracy. Although deemed to provide the highest level of evidence, their clinical value is limited as they can only summarize aggregated data. In these meta-analyses the true variability of the treatment effects cannot be explored to the desired extent, because the meta-analyses cannot distinguish between patients with different clinical profiles. Systematic reviews and meta-analyses based on individual patient data (IPD), described as the ‘gold standard’ for systematic reviews are a promising approach that might overcome these limitations. IPD meta-analyses allow treatment effects and diagnostic accuracy to be estimated at the level of relevant patient subgroups. This enables researchers to investigate the effectiveness of treatment in patients with different profiles. In this article, we address the opportunities of systematic reviews and meta-analyses using IPD in reproductive medicine. We discuss its potential based on three clinical examples: single versus double embryo transfer in IVF, the diagnosis of tubal pathology and the prognostic value of ovarian reserve tests. We propose to show potential advantages of IPD systematic reviews and meta-analyses in providing stratified clinical evidence...
Prediction models are used in reproductive medicine to calculate the probability of pregnancy without treatment, as well as the probability of pregnancy after ovulation induction, intrauterine insemination or in vitro fertilization. The performance of such prediction models is often evaluated with a receiver operating characteristic (ROC) curve. The area under the ROC curve, also known as c-statistic, is then used as a measure of model performance. The value of this c-statistic is low for most prediction models in reproductive medicine. Here, we demonstrate that low values of the c-statistic are to be expected in these prediction models, but we also show that this does not imply that these models are of limited use in clinical practice. The calibration of the model (the correspondence between model-based probabilities and observed pregnancy rates) as well as the availability of a clinically useful distribution of probabilities and the ability to correctly identify the appropriate form of management are more meaningful concepts for model evaluation.; S.F.P.J. Coppus, F. van der Veen, B.C. Opmeer, B.W.J. Mol, and P.M.M. Bossuyt
BACKGROUND Prediction models have been developed in reproductive medicine to help assess the chances of a treatment-(in)dependent pregnancy. Careful evaluation is needed before these models can be implemented in clinical practice. METHODS We systematically searched the literature for papers reporting prediction models in reproductive medicine for three strategies: expectant management, intrauterine insemination (IUI) or in vitro fertilization (IVF). We evaluated which phases of development these models had passed, distinguishing between (i) model derivation, (ii) internal and/or external validation, and (iii) impact analysis. We summarized their performance at external validation in terms of discrimination and calibration. RESULTS We identified 36 papers reporting on 29 prediction models. There were 9 models for the prediction of treatment-independent pregnancy, 3 for the prediction of pregnancy after IUI and 17 for the prediction of pregnancy after IVF. All of the models had completed the phase of model derivation. For six models, the validity of the model was assessed only in the population in which it was developed (internal validation). For eight models, the validity was assessed in populations other than the one in which the model was developed (external validation)...
OBJECTIVE: To evaluate the methodologic quality of economic analyses published in the field of reproductive medicine. DESIGN: Systematic review. SETTING: Centers for reproductive care. PATIENT(S): Infertility patients. INTERVENTION(S): We performed a Medline search to identify economic evaluation studies in reproductive medicine. We included studies that concerned interventions, evaluated costs and effects, and were published in a journal on reproductive medicine, gynecology, or a major general journal from 1997 through May 2011. MAIN OUTCOME MEASURE(S): Number of quality criteria adhered to. RESULT(S): Our search revealed 5,519 articles, of which 85 met our inclusion criteria. Seventy-seven (91%) of the economic analyses were on treatment, six (7%) on diagnosis, and two (2%) on screening. The mean number of quality criteria adhered to was 20 out of 30 items, and only one article met all 30 criteria. The mean number of criteria adhered to was higher if at least one of the authors was from a methodologic or health economics department (mean 23 [n = 30] versus mean 20 [n = 55]). The most common limitations of published economic evaluation studies were in methodology or presentation of incremental analyses, sensitivity analyses, and discounting. CONCLUSION(S): Economic analyses published in the past 15 years in the field of reproductive medicine seldom adhere to all recommended methodologic standards. A large majority of these publications evaluated treatments rather than diagnostic interventions.; Lobke M. Moolenaar...
Background: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. Methods/design: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed...
STUDY QUESTION: How do randomised controlled trials (RCTs) in reproductive medicine report maternal and neonatal outcomes, specifically singleton live birth? SUMMARY ANSWER: Despite the widespread appeal to use singleton live birth as the outcome measure in subfertility trials, 80% of RCTs fail to do so, and fail to report on neonatal and maternal outcomes. WHAT IS KNOWN ALREADY: The aim of reproductive medicine is to assist subfertile couples in their wish to have children. A decade ago it was proposed to use singleton live birth as the outcome measure. We assessed whether clinical research has followed this recommendation, and how neonatal/maternal outcomes are reported. STUDY DESIGN, SIZE, DURATION: A review of the published literature from 1 January 1966 to 31 December 2012 was performed using the Cochrane database. We compared the time periods before and after 2004; the year after ESHRE recommended the use of singleton live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched the Cochrane database for RCTs in reproductive medicine, and recorded the number of studies that used singleton live birth as the outcome measure. We also recorded the reporting neonatal and maternal outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 910 RCTs that reported on fertility treatments...
The aim of reproductive medicine is to help couples with an unfulfilled child wish to have a child by offering them the best treatment option. The choice of treatment reflects effectiveness and safety. While effectiveness refers to the extent to which a treatment increases the chance of a couple in having a baby, safety relates to adverse effects associated with such a treatment. In an attempt to integrate effectiveness and safety, healthy singleton live birth (at term) has been suggested as the ideal outcome measure for evaluative research in reproductive medicine. Although intuitively desirable, this proposal overlooks the fact that assessment of effectiveness and safety in this context cannot be measured as a single outcome. In this paper, we explain why effectiveness and safety outcomes in reproductive medicine should be assessed independently, and later synthesized to inform clinical decision-making.; M. Braakhekke, E.I. Kamphuis, F. Mol, R.J. Norman, S. Bhattacharya, F. van der Veen, and B.W.J. Mol
It is a common feature of debates on the regulation of reproductive medicine to find law portrayed as a crude form of intervention consisting in the imposition of inflexible rules on doctors and medical researchers. This paper argues that this view must be replaced by a more accurate assessment of the law's potential role in the regulation of reproductive medicine. From an analysis of the White Paper on human fertilisation and embryology, and in particular the proposed Statutory Licensing Authority, the author contends that far from being an inflexible method of regulation law can foster discussion and compromise.
The use of the disability-adjusted life year (DALY) as the unit in which to calculate the burden of disease associated with reproductive ill-health has given rise to considerable debate. Criticisms include the failure to address the problem of missing and inadequate epidemiological data, inability to deal adequately with co-morbidities, and lack of transparency in the process of ascribing disability weights to sexual and reproductive health conditions. Many of these criticisms could be addressed within the current DALY framework and a number of suggestions to do so are made. These suggestions include: (1) developing an international research strategy to determine the incidence and prevalence of reproductive ill-health and diseases, including the risk of long-term complications; (2) undertaking a research strategy using case studies, population-based surveillance data and longitudinal studies to identify, evaluate and utilize more of the existing national data sources on sexual and reproductive health; (3) comprehensively mapping the natural history of sexual and reproductive health conditions - in males and in females - and their sequelae, whether physical or psychological; (4) developing valuation instruments that are adaptable for both chronic and acute health states...
Many countries in Latin America and the Caribbean (LAC) are currently reforming their national health sectors and also implementing a comprehensive approach to reproductive health care. Three regional workshops to explore how health sector reform could improve reproductive health services have revealed the inherently complex, competing, and political nature of health sector reform and reproductive health. The objectives of reproductive health care can run parallel to those of health sector reform in that both are concerned with promoting equitable access to high quality care by means of integrated approaches to primary health care, and by the involvement of the public in setting health sector priorities. However, there is a serious risk that health reforms will be driven mainly by financial and/or political considerations and not by the need to improve the quality of health services as a basic human right. With only limited changes to the health systems in many Latin American and Caribbean countries and a handful of examples of positive progress resulting from reforms, the gap between rhetoric and practice remains wide.
It is not clear how policy-making in the field of reproductive health relates to changes associated with programmes for the reform of the health sector in developing countries. There has been little communication between these two areas, yet policy on reproductive health has to be implemented in the context of structural change. This paper examines factors that limit dialogue between the two areas and proposes the following framework for encouraging it: the identification of policy groups and the development of bases for collaborative links between them; the introduction of a common understanding around relevant policy contexts; reaching agreement on compatible aims relating to reproductive health and health sector change; developing causal links between policy content in reproductive health and health sector change as a basis for evidence-based policy-making; and strengthening policy-making structures, systems, skills, and values.