Field Of Reproductive Biology Research Articles

Reproductive biology and medicine 2015--the year in review.

It would be an understatement to suggest that the discoveries in reproductive biology and medicine during 2015 were anything short of remarkable. And to rank these according to potential impact on our field would be a disservice to the groups that have persevered in tackling fundamental questions with the most sophisticated of techniques ensconced in the biomedical research enterprise of this decade. And so, with a measure of humility, a sense of awe, and the poetic license liberally taken by your EIC, a short summary of what might be considered a sentinel of what reproductive medicine may look like in the coming years is provided below. Progress in the area of germline stem cells continues to dominate a research landscape aiming to define the embryonic origins of primordial germ cells (PGCs) in molecular terms while at the same time nudging this line of research into the domain of treating infertility in men and women. That the horizon indeed holds the promise of making germline stem cells in vivo and in vitro is evidenced by the latest contributions from the laboratory of Surani and colleagues who have now mapped a molecular signature for the production of PGCs in humans (Tang et al., A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Cell. 2015 Jun 4;161(6):1453–67. doi: 10. 1016/j.cell.2015.04.053. http://www.ncbi.nlm.nih.gov/ pubmed/26046444). And the continuing quest for ways to obtain the best quality stem cells, which the field of regenerative medicine has been waiting for (as human ARTs sets the gold standards for quality embryo production), has taken an interesting twist of fate with a recent publication from the laboratory of Susan Fisher and her colleagues at UCSF (Zdavkovic et al., Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification. http://dev.biologists.org/lookup/ doi/10.1242/dev.122846). Taking single blastomeres from four 8-cell and one 12-cell embryos from a single individual lead to the derivation of ten ES cell lines, each of which displayed unique transcriptomic and protein heterogeneities, providing new insights into the allocation of cell lineages in the human embryo. Gene editing in human embryos captured the attention of many this past year. The power of CRISPR/Cas9 entered the arena of reproductive medicine with much fanfare as a result of the publication by Liang and colleagues proof-of-principle case using ART generated three PN zygotes (Liang et al., CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015 May;6(5):363–72. doi: 10.1007/ s13238-015-0153-5. Epub 2015 Apr 18. http://www.ncbi. nlm.nih.gov/pubmed/25894090). This work sparked renewed interest in prospects for genetic engineering but in tandem has brought the level of discourse to new heights in light of ethical and societal implications that are only now being subject to the degree of scrutiny they deserve. That RNAs of the many varieties now understood to have important physiological functions have been catching their fair share of attention at both the basic and clinical levels has come as no surprise. From the Kravetz and Diamond groups, this year came the exciting finding that certain spermassociated RNAs detected by next gen sequencing could be Capsule 2015 was a year of unprecedented discovery in the fields of reproductive biology and medicine. Here, we take note of ten publications that have drawn upon technological advances of the past decade to bring new ways of thinking about old problems into the realm of human ARTs and reproductive genetics.

Telomere homeostasis in mammalian germ cells: a review.

Telomeres protect against genome instability and participate in chromosomal movements during gametogenesis, especially in meiosis. Thus, maintaining telomere structure and telomeric length is essential to both cell integrity and the production of germ cells. As a result, alteration of telomere homeostasis in the germ line may result in the generation of aneuploid gametes or gametogenesis disruption, triggering fertility problems. In this work, we provide an overview on fundamental aspects of the literature regarding the organization of telomeres in mammalian germ cells, paying special attention to telomere structure and function, as well as the maintenance of telomeric length during gametogenesis. Moreover, we discuss the different roles recently described for telomerase and TERRA in maintaining telomere functionality. Finally, we review how new findings in the field of reproductive biology underscore the role of telomere homeostasis as a potential biomarker for infertility. Overall, we anticipate that the study of telomere stability and equilibrium will contribute to improve diagnoses of patients; assess the risk of infertility in the offspring; and in turn, find new treatments.

Critical Review: Immunomodulation by Seminal Factors and Implications for Male-to-Female HIV-1 Transmission.

The role of semen in heterosexual transmission of the HIV-1 has been marginally viewed as an inert vehicle for the delivery of virus. However, studies from the field of reproductive biology have made it clear that seminal fluid is a complex and dynamic medium containing high concentrations of factors that play key roles in modulating the local immune response in the female reproductive tract during fertilization and embryogenesis. It is therefore strongly implied that the same seminal factors responsible for guiding the immune response in reproduction also play a role in male-to-female transmission of HIV-1. To begin to understand how these factors affect male-to-female HIV-1 transmission, multiple studies have comparatively profiled the contents of seminal fluid collected from uninfected and HIV-1-infected men. This review provides an overview of these studies, as well as a discussion of the potential impact of semen on HIV-1 transmission.

Computer-generated ovaries to assist follicle counting experiments.

Precise estimation of the number of follicles in ovaries is of key importance in the field of reproductive biology, both from a developmental point of view, where follicle numbers are determined at specific time points, as well as from a therapeutic perspective, determining the adverse effects of environmental toxins and cancer chemotherapeutics on the reproductive system. The two main factors affecting follicle number estimates are the sampling method and the variation in follicle numbers within animals of the same strain, due to biological variability. This study aims at assessing the effect of these two factors, when estimating ovarian follicle numbers of neonatal mice. We developed computer algorithms, which generate models of neonatal mouse ovaries (simulated ovaries), with characteristics derived from experimental measurements already available in the published literature. The simulated ovaries are used to reproduce in-silico counting experiments based on unbiased stereological techniques; the proposed approach provides the necessary number of ovaries and sampling frequency to be used in the experiments given a specific biological variability and a desirable degree of accuracy. The simulated ovary is a novel, versatile tool which can be used in the planning phase of experiments to estimate the expected number of animals and workload, ensuring appropriate statistical power of the resulting measurements. Moreover, the idea of the simulated ovary can be applied to other organs made up of large numbers of individual functional units.

La vitrification ovocytaire : un outil d’avenir

Ovocyte vitrification was finally authorized by the new law voted in July 2011 upon the revision of the French bioethics law. Expected for 30 years, cryopreservation of female gametes had a major impact on Assisted Reproductive Technologies (ART) practice worldwide and in our country. It brought tremendous changes in the field of reproductive biology, from intraconjugal infertility management to gamete donation, through autologous cryopreservation for fertility preservation. Although it appears to be "obvious", ovocyte vitrification seems to be barely used as a routine technique in French IVF laboratories. We will discuss the events that led to the present situation. We will also tackle the expected benefits of ovocyte vitrification especially as an alternative to embryo freezing.

New Trends in Assisted Reproduction Techniques: Cryopreservation, In vitro Fertilization, Intracytoplasmic Sperm Injection and Physiological Intracytoplasmic Sperm Injection

Since that historically the first human birth was registered through in vitro fertilization in 1978, the improvement and creation of new assisted reproduction techniques such as intracytoplasmic sperm injection and physiological intracytoplasmic sperm injection have become of great importance nowadays. Louise Brown was the first baby conceived through in vitro fertilization in England. Since then, several worldwide studies have reported human and domestic animals outcomes. This fact has solved human fertility problems creating new ways of conceiving. Before the success with in vitro fertilization, other assisted reproduction techniques such as cryopreservation were developed. Spermatozoa were the first mammalian cells to be cryopreserved. These events revolutionized all the research in the field of reproductive biology. However, in terms of cryopreservation, intense work needs to be intended since low recovery rates are still reported. The improvement of vitrification-warming procedures is highly important in order to increase embryo development and outcomes. In domestic species, porcine oocytes are the most sensitive cells during vitrification. The future of vitrification success is promising; therefore cryobiologists have a commitment in the field of assisted reproduction. The aim of this review was the acknowledgement of the current status of assisted reproduction techniques, its application, progress and future prospects.

Current scenario on genetic basis of infertility- A review

Infertility is an emerging major health issue affecting the physical, psychological and social status of the general population across the globe. There are innumerable causes of infertility, viz., ovarian and testicular disorders, advanced maternal age, obesity, chromosomal abnormalities etc. Most of these causes are linked to the genetic disorders. With recent advances in the field of reproductive biology, it has become imperative to have a concise knowledge of the genetic basis of infertility, for better outcome in Assisted Reproductive Techniques (ART).

Ovarian stem cells: From basic to clinical applications.

The field of reproductive biology has undergone significant developments in the last decade. The notion that there is a fixed reserve pool of oocytes before birth was established by Zuckerman in 1951. However, in 2004, an article published in nature challenged this central dogma of mammalian reproductive biology. Tilly's group reported the existence of ovarian germline stem cells (GSCs) in postnatal ovaries of mice and suggested that the bone marrow could be an extragonadal source of ovarian GSCs. These findings were strongly criticized; however, several independent groups have since successfully isolated and characterized ovarian GSCs in postnatal mice. The ovarian GSCs are located in the ovarian surface epithelium and express markers of undifferentiated GSCs. When transplanted into mouse ovaries, mouse ovarian GSCs could differentiate and produce embryos and offspring. Similarly, in a recent study, ovarian GSCs were found to be present in the ovaries of women of reproductive age. Conversely, there is increasing evidence that stem cells responsible for maintaining a healthy state in normal tissue may be a source of some cancers, including ovarian cancer. Cancer stem cells (CSCs) have been found in many tissues, including ovaries. Some researchers have suggested that ovarian cancer may be a result of the transformation and dysfunction of ovarian GSCs with self-renewal properties. Drug resistant and metastasis-generating CSCs are responsible for many important problems affecting ovarian cancer patients. Therefore, the identification of CSCs will provide opportunities for the development of new therapeutic strategies for treatments for infertility and ovarian cancer. In this article, we summarize the current understanding of ovarian GSCs in adult mammals, and we also discuss whether there is a relationship between GSCs and CSCs.

Core body temperature is not a reliable parameter to follow the reproductive cycle in female marmoset monkey (<i>Callithrix jacchus</i>)

Abstract. Marmosets represent an attractive and widely used animal species in biomedical research, and the routine monitoring of female reproductive cycles is often mandatory in the fields of reproductive biology and stem cell research. Today, the established method for the reliable detection of ovulation is the determination of progesterone concentrations from blood samples. This method is based on relatively frequent handling and blood collections; therefore, less invasive alternatives would help to reduce stress on the animals. Here, we investigated whether the core body temperature of marmosets would show a correlation with cycle-dependent hormonal fluctuations, as has been described for humans and other primate species. In particular, the objective was to investigate whether the telemetric recording of core body temperature could replace progesterone measurements as a reliable, less invasive method for the detection of ovulation in these animals. Here we show that the core body temperature parameters in female marmosets were characterized by frequent variations, but they were not related to particular days or phases during the reproductive cycle. Therefore, the recording of core body temperature in our controlled standard experimental setting is not an appropriate method to monitor the reproductive cycle in female marmosets, and cannot replace serum progesterone measurement as a state-of-the-art method.

睾丸免疫豁免与天然免疫

Orchitis is one of the etiological factors of male infertility. The testis is a remarkable immune privileged organ and represents a special immunological environment. Immune privilege implies a small number of tissues in the body where allo- and auto-antigens are tolerated to prevent tissue damage and dysfunction by the systemic immune response. Immune privileged sites in mammals include the testis, brain, eyes and pregnant uterus. The two main functions of the testis are sperm production and androgen synthesis. Since the production of mature sperm occurs exclusively post-puberty, long after immune competence is established during fetal and early neonatal life, a large number of auto-antigens synthesized by germ cells are immunogenic. However, these germ cell auto-antigens do not induce immune responses within the testis, because of "immune privilege". Testicular immune privilege status is maintained by a combination of physical structures, testicular cell properties and local immune suppressive molecules. However, the testis can be infected by invading microbial pathogens. To overcome immune privilege and mount an appropriate local immune response to protect the testis from infection, tissue-specific cells have adopted effective innate immune functions against invading pathogens. Balance of the testicular immunological environment is necessary for tissue functions. Breakdown of immune homeostasis in the testis may lead to chronic orchitis, a significant etiological factor for male infertility. The mechanisms underlying testicular immune privilege and innate immunity are important issues in the field of reproductive biology. This review highlights the progress of studies on these issues, and outlines topics that are worthy of further investigation.

Regulation of decidualization and angiogenesis in the human endometrium: mini review.

The human endometrium is a dynamic tissue that undergoes regular cycles of menstruation, menstrual repair, proliferation and secretory differentiation in response to hypoxia and the female sex hormones. We identified new target genes that are regulated by progesterone during the decidualization of human endometrial stromal cells (ESC), including interleukin-15 (IL-15), fibulin-1 (FBLN-1), and heart and neural crest derivatives expressed transcript 2 (HAND2). IL-15 is deeply involved in the hormonal control of the human endometrium by progesterone and may be important in embryo implantation. FBLN-1 has been shown to be an important extracellular matrix that mediates progesterone action in human ESC differentiation toward implantation. Moreover, progestin-induced HAND2 is a transcription factor that contributes to the increased levels of FBLN-1 in human ESC. Several mediators, including vascular endothelial growth factor (VEGF), angiopoietin (ANGPT) and stromal cell-derived factor 1 (SDF-1), regulate human endometrial angiogenesis. Hypoxia increased the expression of VEGF and decreased the expression of SDF-1 in ESCs. Furthermore, hypoxia reduced ANGPT1 levels in ESC; however, ANGPT2 levels were unaffected. Estradiol simultaneously induced the expressions of VEGF and SDF-1, suppressing ANGPT1 production. Therefore, hypoxia and estradiol caused an increase in the ANGPT2/ANGPT1 ratio. Hypoxia and female sex hormones are involved in the regulation of angiogenic factors in an independent manner in human ESC. Analysis of the process of decidualization and angiogenesis in the human endometrium would provide useful information for the fields of reproductive biology, regenerative medicine and tissue engineering.

Keeping reproductive science visible, viable, and valuable—a call to rethink how we publish

Keeping reproductive science visible, viable, and valuable—a call to rethink how we publish

A small field for fertile science: the low visibility of reproductive science in high impact journals

Our success as a field and as individuals in reproductive science and medicine relies on our ability to produce high quality work that has broad visibility and impact. A common metric for assessing such success is the quantity of publications that are published in journals with high impact factors. It is unclear, however, how frequently work related to reproductive science and medicine actually appears in what are considered the highest impact journals. To address this gap in knowledge, we first determined how the field of reproductive biology in general compared to other research areas in terms of composite journal impact factor. Second, using a targeted search approach in the PubMed database, we examined the relationship between a journal's impact factor and the number of reproductive research articles published per journal issue. We found that compared to other major scientific disciplines, our field lacks journals with impact factors above 4. In addition, primary original research articles on reproduction-irrespective of male or female search terms-do not appear often in high impact journals. Instead, there is an increased percentage of secondary reproductive literature in high impact journals compared to topic-specific journals of lower impact. There are likely several explanations for why reproductive science and medicine has low visibility, including the field's small relative size, its lack of a specific disease and associated strong advocacy, and its surrounding social, ethical, and political unease. Nevertheless, there are concrete actions we can take to minimize the role of impact factor in our evaluation while simultaneously increasing influence through global awareness of the importance and need for reproductive research.

Cryopreservation in ART and concerns with contamination during cryobanking.

The cryopreservation of gametes and embryos is vital to numerous fields of reproductive biology, including assisted human reproduction. With improved culture conditions, there are an increasing number of embryos to cryopreserve for potential use in subsequent cycles. Many of the gametes and embryos in human IVF are cryopreserved in open systems. Because liquid nitrogen is not sterile, concerns have been raised with regard to contamination from the liquid nitrogen and also cross-contamination between patients' germplasm. Human gamete and embryo cryopreservation are discussed, with recommendations on how to minimize and eliminate contamination, emphasizing the benefits of closed vitrification devices.

Factors that affect oocyte vitrification in small ruminants

At the end of its growth, the mammalian oocyte, include in preovulatory follicle, is the largest cell of the organism, with about 120 µm in diameter. The size of oocyte, together with the specific arrangement of its organels and cytoskeleton, makes a real challenge for cryopreservation techniques. For such large cell, methods that do not require equilibrium to cryopreservation, such as vitrification, are more promising. It is important to highlight that the cryopreservation of oocytes is more difficult than zygotes or later stage embryos and this technique is a challenging task because of oocyte sensitive nature to chilling and toxic effects of cryoprotectants. However, the development of a reliable method for oocyte cryopreservation would be an important advance in the field of reproductive biology for the preservation of genetic resources. The vitrification of mammalian oocytes is influenced by many variables, such as different cryoprotectants, vitrification techniques, presence or absence of cumulus cells, the oocyte structure, metabolism (such as level of lipid storage) and meiotic stage. Thus, all these factors should be considered to optimize the techniques and adapt them to oocytes from each species. Therefore, the present review aims to describe the main factors that affect oocyte vitrification in sheep and goats, reporting the main findings in both species, as well as perspectives of future improvements.

Development of a Methodology for and Assessment of Pulsatile Luteinizing Hormone Secretion in Juvenile and Adult Male Mice

Current methodology to monitor pulsatile LH release in mice is limited by inadequate assay sensitivity, resulting in the need for collection of large blood volumes. Thus, assessment of pulsatile LH secretion in mice remains highly challenging, and observations are limited to adult mice. To address this, we developed a highly sensitive ELISA for assessment of mouse LH concentrations in small fractions of whole blood. We demonstrate that this assay is capable of reliably detecting LH down to a theoretical limit of 0.117 ng/mL in a 2-μL fraction of whole blood. Using an established frequent blood collection procedure, we validated the accuracy of this method by determining the pulsatile LH secretion in early-adult (10 weeks old) C57BL6/J male mice. Data demonstrate regular pulsatile release of LH, with peaks in LH secretion rarely exceeding 3 ng/mL. Moreover, assessment of LH release in Gpr54 knockout mice demonstrates the lack of pulsatile LH release after the loss of kisspeptin-mediated pubertal maturation. We next determined age-associated changes in pulsatile LH secretion by assessment of LH secretion in prepubertal (28 days old) C57BL6/J male mice and repeated assessment in the same mice in adulthood (120 days old). Data demonstrate that the rise in total LH secretion in mice after pubertal maturation occurs along with an overall rise in the pulsatile LH secretion rate. This was coupled with a significant increase in the number of LH secretory events (number of pulses). In addition, we observed a decrease in the clearance (increased half-life) and a decrease in the regularity (approximate entropy) of LH release. This method will be of wide general utility within the field of reproductive biology.

Purification of Oogonial Stem Cells From Adult Mouse and Human Ovaries: An Assessment of the Literature and a View Toward the Future

Contemporary claims that mitotically active female germ line or oogonial stem cells (OSCs) exist and support oogenesis during postnatal life in mammals have been debated in the field of reproductive biology since March 2004, when a mouse study posed the first serious challenge to the dogma of a fixed pool of oocytes being endowed at birth in more than 50 years. Other studies have since been put forth that further question the validity of this dogma, including the isolation of OSCs from neonatal and adult mouse ovaries by 4 independent groups using multiple strategies. Two of these groups also reported that isolated mouse OSCs, once transplanted back into ovaries of adult female mice, differentiate into fully functional eggs that ovulate, fertilize, and produce healthy embryos and offspring. Arguably, one of the most significant advances in this emerging field was provided by a new research study published this year, which reported the successful isolation and functional characterization of OSCs from ovaries of reproductive age women. Two commentaries on this latest work, one cautiously supportive and one highly skeptical, were published soon afterward. This article evaluates the current literature regarding postnatal oogenesis in mammals and discusses important next steps for future work on OSC biology and function.

After 65 years, research is still fun.

In 1946, at the end of World War II, I entered graduate school at Cornell University, where I remained for 44 years. During that time, my laboratory produced more than 300 publications in the field of reproductive biology, including studies on nutrition and reproduction, the role of the hypothalamus in pituitary gonadotropin release, corpus luteum formation and function, hormone assays, and estrous cycle synchronization. At age seventy, I retired from Cornell and accepted the Gordon Cain Endowed Professorship at Louisiana State University, where I continued my work on the bovine corpus luteum and added research on the collection, maturation, in vitro fertilization, and culture of bovine oocytes. In 1994, I moved to the Pennington Biomedical Research Center and soon thereafter started the research that led to development of the lytic peptide-gonadotropin conjugates, which target and destroy cancer cell membranes. I am continuing my work on the development of targeted cancer cell drugs and, yes, research is still fun!

Advances in embryo selection methods

Despite many recent advances in the field of reproductive biology and medicine, the efficiency of in vitro fertilization procedures remains relatively low. There is a need for a reliable and non-invasive method of embryo selection to ensure that only embryos with the highest developmental potential are chosen for transfer to mothers-to-be. Here, we compare various methods currently used for assessing embryonic viability, such as examination of embryonic morphology, quality of the genetic material, or metabolism. Additionally, we discuss novel procedures for embryonic assessment based on advanced time-lapse imaging techniques, which show great promise and may lead to increased in vitro fertilization efficiencies.

The Evolution of Sex-Related Traits and Genes

The Evolution of Sex-Related Traits and Genes