The sixth vital sign: what reproduction tells us about overall health. Proceedings from a NICHD/CDC workshop.

STUDY QUESTION: Does the fertility status of an individual act as a biomarker for their future health? SUMMARY ANSWER: Data support an association between reproductive health and overall health for men and women. WHAT IS ALREADY KNOWN: Various chronic conditions, such as diabetes, obesity and cancer, can compromise fertility, but there are limited data for the converse situation, in which fertility status can influence or act as a marker for future health. Data reveal an association between infertility and incident cardiovascular disease and cancer in both men and women. STUDY DESIGN SIZE AND DURATION: A National Institute of Child Health and Human Development-Centers for Disease Control and Prevention workshop in April 2016 was convened that brought together experts in both somatic diseases and conditions, and reproductive health. Goals of the workshop included obtaining information about the current state of the science linking fertility status and overall health, identifying potential gaps and barriers limiting progress in the field, and outlining the highest priorities to move the field forward. PARTICIPANTS/MATERIALS SETTING AND METHODS: Approximately 40 experts participated in the workshop. MAIN RESULTS AND THE ROLE OF CHANCE: While the etiology remains uncertain for infertility, there is evidence for an association between male and female infertility and later health. The current body of evidence suggests four main categories for considering biological explanations: genetic factors, hormonal factors, in utero factors, and lifestyle/health factors. These categories would be key to include in future studies to develop a comprehensive and possibly standardized look at fertility status and overall health. Several themes emerged from the group discussion including strategies for maximizing use of existing resources and databases, the need for additional epidemiologic studies and public health surveillance, development of strategies to frame research so results could ultimately influence clinical practice, and the identification of short and long-term goals and the best means to achieve them. LIMITATIONS REASONS FOR CAUTION: Further research may not indicate an association between fertility status and overall health. WIDER IMPLICATIONS OF THE FINDINGS: Currently medical care is compartmentalized. Reproductive medicine physicians treat patients for a short period of time before they transition to others for future care. Going forward, it is critical to take an interdisciplinary patient care approach that would involve experts in a broad range of medical specialties in order to more fully understand the complex interrelationships between fertility and overall health. If infertility is confirmed as an early marker of chronic disease then screening practices could be adjusted, as they are for patients with a family history of malignancy. STUDY FUNDING/COMPETING INTERESTS: Funding for the workshop was provided by the Fertility and Infertility Branch, National Institute of Child Health and Human Development, National Institutes of Health and the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control. There are no conflicts of interest to declare. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention or the National Institutes of Health. TRIAL REGISTRATION NUMBER: Not applicable.

Molecular classification of endometriosis and disease stage using high-dimensional genomic data.

Endometriosis (E), an estrogen-dependent, progesterone-resistant, inflammatory disorder, affects 10% of reproductive-age women. It is diagnosed and staged at surgery, resulting in an 11-year latency from symptom onset to diagnosis, underscoring the need for less invasive, less expensive approaches. Because the uterine lining (endometrium) in women with E has altered molecular profiles, we tested whether molecular classification of this tissue can distinguish and stage disease. We developed classifiers using genomic data from n = 148 archived endometrial samples from women with E or without E (normal controls or with other common uterine/pelvic pathologies) across the menstrual cycle and evaluated their performance on independent sample sets. Classifiers were trained separately on samples in specific hormonal milieu, using margin tree classification, and accuracies were scored on independent validation samples. Classification of samples from women with E or no E involved 2 binary decisions, each based on expression of specific genes. These first distinguished presence or absence of uterine/pelvic pathology and then no E from E, with the latter further classified according to severity (minimal/mild or moderate/severe). Best performing classifiers identified E with 90%-100% accuracy, were cycle phase-specific or independent, and used relatively few genes to determine disease and severity. Differential gene expression and pathway analyses revealed immune activation, altered steroid and thyroid hormone signaling/metabolism, and growth factor signaling in endometrium of women with E. Similar findings were observed with other disorders vs controls. Thus, classifier analysis of genomic data from endometrium can detect and stage pelvic E with high accuracy, dependent or independent of hormonal milieu. We propose that limited classifier candidate genes are of high value in developing diagnostics and identifying therapeutic targets. Discovery of endometrial molecular differences in the presence of E and other uterine/pelvic pathologies raises the broader biological question of their impact on the steroid hormone response and normal functions of this tissue.

Providing research and research training infrastructures for clinical research in the reproductive sciences.

The Reproductive Sciences Branch of the National Institutes of Child Health and Human Development has created pioneering new research and research training programs that address the impending shortage of physician-scientists in obstetrics, gynecology, and women's health and the need to bolster translational and clinical research. This article provides a brief overview of the Specialized Cooperative Centers Program in Reproduction Research, the National Cooperative Program for Infertility Research, the Reproductive Medicine Network, the Reproductive Scientist Development Program, the Women's Reproductive Health Research Career Development Program, and the Contraception and Infertility Research Loan Repayment Program and describes how these programs collectively create an infrastructure to promote the next generation of physician-scientists and to provide an information exchange between basic and clinical investigators. A key component in increasing the number of clinical investigators is the Contraception and Infertility Research Loan Repayment Program. This program has enabled clinicians to be involved in research without having to be concerned about educational loan debt. Other component programs provide basic/translational, clinical hypothesis-oriented research and clinical trials research infrastructure. The programs created are individually strong and collectively poised to support translational and clinical research efforts and to build a well-trained cadre of physician-scientists. The collective use of these types of programs is proposed as a model for the National Institutes of Health.