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Posts Tagged ‘infertility’

Regulatory T cells (Tregs) are important for sperm tolerance and male fertility

Posted in Autoimmune Inflammatory DIseases, Developmental biology, Diagnostic Immunology, Human Antibody Response, Human Immune System in Health and in Disease, Immunodiagnostics, Immunology, Immunotherapy, Innovation in Immunology Diagnostics, Personal Health Applications: Tech Innovations serves HealhCare, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Preimplantation Genetic Diagnosis and Reproductive Genomics, Protection Against Autoimmune Disease, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, Tolerance-inducing Autoimmune Disease Therapeutics, tagged , , , , , , , on September 11, 2023| Leave a Comment »

Regulatory T cells (Tregs) are important for sperm tolerance and male fertility

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Regulatory T cells (Tregs) are specialized immune cells that modulate tissue homeostasis. They are a specialized subset of T lymphocytes that function as suppressive immune cells and inhibit various elements of immune response in vitro and in vivo. While there are constraints on the number or function of Tregs which can be exploited to evoke an effective anti-tumor response, sufficient expansion of Tregs is essential for successful organ transplantation and for promoting tolerance of self and foreign antigens. Current studies have provided evidence that a defect in the number or function of Tregs contributes to the etiology of several reproductive diseases.

In the male reproductive tract, prevention of autoimmune responses against antigenic spermatozoa, while ensuring protection against stressors, is a key determinant of fertility. Using an autoimmunity-induced model, it was uncovered that the role of Tregs in maintaining the tolerogenic state of the testis and epididymis. The loss of tolerance induced an exacerbated immune cell infiltration and the development of anti-sperm antibodies, which caused severe male subfertility. By identifying immunoregulatory mechanisms in the testis and epididymis.

Tregs modulate tissue homeostatic processes and immune responses. Understanding tissue-Treg biology will contribute to developing precision-targeting treatment strategies. Here, it was reported that Tregs maintain the tolerogenic state of the testis and epididymis, where sperm are produced and mature. It was found that Treg depletion induces severe autoimmune orchitis and epididymitis, manifested by an exacerbated immune cell infiltration [CD4 T cells, monocytes, and mononuclear phagocytes (MPs)] and the development of anti-sperm antibodies (ASA).

In Treg-depleted mice, MPs increased projections toward the epididymal lumen as well as invading the lumen. ASA-bound sperm enhance sperm agglutination and might facilitate sperm phagocytosis. Tolerance breakdown impaired epididymal epithelial function and altered extracellular vesicle cargo, both of which play crucial roles in the acquisition of sperm fertilizing ability and subsequent embryo development. The affected mice had reduced sperm number and motility and severe fertility defects.

Deciphering these immunoregulatory mechanisms may lead to the development of therapies for infertility and identifying potential targets for immuno-contraception. Ultimately, such knowledge fills gaps related to reproductive mucosa, which is an understudied facet of human male health.

References:

https://www.pnas.org/doi/10.1073/pnas.2306797120

https://pubmed.ncbi.nlm.nih.gov/24048122/

https://pubmed.ncbi.nlm.nih.gov/34845322/

https://pubmed.ncbi.nlm.nih.gov/34845322/

https://pubmed.ncbi.nlm.nih.gov/29648649/

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Sperm epigenetic clock and pregnancy outcomes

Posted in Biological Engineering, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell Processing System in Cell Therapy Process Development, Epigenetics and Environmental Factors, Genomic Endocrinology, Human aging, Methylation, MicroEngineering Cell-Tissue & Systems, Molecular Genetics & Pharmaceutical, Population Health Management, Genetics & Pharmaceutical, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , , , on May 14, 2022| 1 Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Infertility has been primarily treated as a female predicament but around one-half of infertility cases can be tracked to male factors. Clinically, male infertility is typically determined using measures of semen quality recommended by World Health Organization (WHO). A major limitation, however, is that standard semen analyses are relatively poor predictors of reproductive capacity and success. Despite major advances in understanding the molecular and cellular functions in sperm over the last several decades, semen analyses remain the primary method to assess male fecundity and fertility.

Chronological age is a significant determinant of human fecundity and fertility. The disease burden of infertility is likely to continue to rise as parental age at the time of conception has been steadily increasing. While the emphasis has been on the effects of advanced maternal age on adverse reproductive and offspring health, new evidence suggests that, irrespective of maternal age, higher male age contributes to longer time-to-conception, poor pregnancy outcomes and adverse health of the offspring in later life. The effect of chronological age on the genomic landscape of DNA methylation is profound and likely occurs through the accumulation of maintenance errors of DNA methylation over the lifespan, which have been originally described as epigenetic drift.

In recent years, the strong relation between age and DNA methylation profiles has enabled the development of statistical models to estimate biological age in most somatic tissue via different epigenetic ‘clock’ metrics, such as DNA methylation age and epigenetic age acceleration, which describe the degree to which predicted biological age deviates from chronological age. In turn, these epigenetic clock metrics have emerged as novel biomarkers of a host of phenotypes such as allergy and asthma in children, early menopause, increased incidence of cancer types and cardiovascular-related diseases, frailty and cognitive decline in adults. They also display good predictive ability for cancer, cardiovascular and all-cause mortality.

Epigenetic clock metrics are powerful tools to better understand the aging process in somatic tissue as well as their associations with adverse disease outcomes and mortality. Only a few studies have constructed epigenetic clocks specific to male germ cells and only one study reported that smokers trended toward an increased epigenetic age compared to non-smokers. These results indicate that sperm epigenetic clocks hold promise as a novel biomarker for reproductive health and/or environmental exposures. However, the relation between sperm epigenetic clocks and reproductive outcomes has not been examined.

There is a critical need for new measures of male fecundity for assessing overall reproductive success among couples in the general population. Data shows that sperm epigenetic clocks may fulfill this need as a novel biomarker that predicts pregnancy success among couples not seeking fertility treatment. Such a summary measure of sperm biological age is of clinical importance as it allows couples in the general population to realize their probability of achieving pregnancy during natural intercourse, thereby informing and expediting potential infertility treatment decisions. With the ability to customize high throughput DNA methylation arrays and capture sequencing approaches, the integration of the epigenetic clocks as part of standard clinical care can enhance our understanding of idiopathic infertility and the paternal contribution to reproductive success and offspring health.

References:

https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deac084/6583111?login=false

https://pubmed.ncbi.nlm.nih.gov/33317634/

https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0656-7

https://pubmed.ncbi.nlm.nih.gov/19319879/

https://pubmed.ncbi.nlm.nih.gov/31901222/

https://pubmed.ncbi.nlm.nih.gov/25928123/

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Embryo Stem Cells Out of Skin

Posted in Embryology, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged , , , , , on May 8, 2019| Leave a Comment »

Embryo Stem Cells Out of Skin

Reporter: Irina Robu, PhD

Researchers at Hebrew University identified a set of genes able to transform murine skin cells into three cell types such as the embryo itself, the placenta and extraembryonic tissue i.e. umbilical cord which was published in the journal Cell Stem Cell.

Dr. Oren Ram, Institute of Life Science at Hebrew University, Prof. Tommy Kaplan, School of Computer Science and Engineering found a new combination of five genes that once inserted into skin cells, reprogram the cells into each of three early embryonic cell types. Researchers identified that the gene “Eomes” pushes the cell toward placental stem-cell identity and placental development, whereas the “Esrrb” gene arranges fetus stem cells development through the temporary procurement of an extraembryonic stem cell identity.The team used this to examine the molecular forces that oversee cell fate decisions for skin cell reprogramming and the natural process of embryonic development.

Even though this groundbreaking research could provide a path toward creating entire human embryos from human cell skin cells without need for sperm of organs, that is still a long way in the future. However, for now this work can have large implications for modeling embryonic disease and placental dysfunctions in addition to solving infertility problems by creating human embryos in a petri dish.

SOURCE
https://www.jpost.com/OMG/A-baby-from-skin-cells-Israeli-team-makes-embryo-stem-cells-out-of-skin-588531

 

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The viability of Anti-Müllerian Hormone (AMH) level as fertility marker

Posted in Biomedical Measurement Science, Cell Biology, Cell Biology, Signaling & Cell Circuits, Clinical Diagnostics, Diagnostics and Lab Tests, Endocrine Diseases, Evidence-based decision-making, Human aging, Methods, Population Health Management, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , , , on November 15, 2017| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Anti-Müllerian Hormone (AMH), is secreted by growing follicles that contains the egg or ovum. According to regular practice low AMH and high Follicle Stimulating Hormone (FSH) are generally considered as indicators of diminished egg quantity in a female. But, there are several cases the female conceived absolutely normally without any support even after low AMH was reported.

 

Therefore, a new research published in the Journal of the American Medical Association declares that AMH doesn’t dictate a woman’s reproductive potential. Although AMH testing is one of the most common ways that doctors assess a woman’s fertility. Present research says that all it takes is one egg each cycle and AMH is not a marker of whether a female can or cannot become pregnant. So, for women who haven’t yet tried to get pregnant and who are wondering whether they are fertile, an AMH value isn’t going to be helpful in that context. In addition, AMH is not necessarily a good marker to predict that whether one has to cryopreserve her eggs. So, practically doctors don’t yet have a way to definitively predict egg quality or a woman’s long-term ability to conceive, but age is obviously one of the most important factors.

 

The above mentioned study followed 750 women between the ages of 30 and 44 who had been trying to conceive for three months or less. During the 12-month observation period, those with low AMH values of less than 0.7 were not less likely to conceive than those who had normal AMH values. The study had various limitations, however, that are worth noting. The researchers only included women who did not have a history of infertility. Women who sought fertility treatments (about 6 percent) were withdrawn. And only 12 percent of the women were in the 38-to-44 age range. In addition, the number of live births was unavailable.

 

Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood FSH tests or AMH levels to assess natural fertility for women with these characteristics. The researchers’ next want to see whether low AMH is associated with a higher risk of miscarriage among the women who conceived.

 

Although AMH testing isn’t designed to be an overall gauge of a woman’s fertility, it can still provide valuable information, especially for women who are infertile and seeking treatment. It can assist in diagnosing polycystic ovarian syndrome, and identify when a woman is getting closer to menopause. Previous research also showed that AMH is good predictor of a woman’s response to ovarian stimulation for in vitro fertilization and therefore it can predict the probability of conceiving via in vitro fertilization (I.V.F.).

 

References:

 

https://jamanetwork.com/journals/jama/article-abstract/2656811?JamaNetworkReader=True

 

https://www.nytimes.com/2017/10/16/health/fertility-test-ovarian-reserve.html

 

https://academic.oup.com/humrep/article/26/11/2925/656065

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339896/

 

https://www.ncbi.nlm.nih.gov/pubmed/27179263

 

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Cellular switch molecule for sperm motility control: a novel target for male contraception and infertility treatments

Posted in Biomarkers & Medical Diagnostics, Ca2+ triggered activation, Calcium Signaling, Cell Biology, Cell Biology, Signaling & Cell Circuits, Clinical Diagnostics, Endocrine Diseases, Population Health Management, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, Signaling, Signaling & Cell Circuits, tagged , , , , , on April 4, 2016| Leave a Comment »

Cellular switch molecule for sperm motility control: a novel target for male contraception and infertility treatments

Reporter and Curator: Sudipta Saha, Ph.D.

 

Researchers have discovered the cellular switch that boosts the activity of sperm cells so that they can travel to the egg.  The finding may lead to new options for male contraception as well as treatments for infertility resulting from problems with sperm mobility.

Inside the male reproductive tract, mature sperm are capable of limited movement. This limited movement, however, is not enough to propel them toward the egg when they enter the female reproductive tract. To begin their journey, they must first be activated by the hormone progesterone, which is released by the egg.

The researchers reported that the molecule to which progesterone must bind is the enzyme alpha/beta hydrolase domain containing protein 2 (ABHD2), found in the sperm cell’s outer membrane. Similarly, strategies to bypass or enhance the enzyme might provide therapies for treating infertility resulting from sperm that lack movement capability.

Before a sperm can transition to the hyper-active phase, calcium must pass through the cell’s outer membrane and enter the flagella, the tail-like appendage the cell uses to propel itself. The sperm protein known as CatSper joins with similar proteins in the flagella to allow the entry of calcium.

When the researchers undertook the current study, it was not known whether progesterone interacted directly with CatSper to trigger the calcium influx, or acted on some other molecule (which, in turn, acted on CatSper). Before treating sperm with progesterone, the researchers exposed them to a chemical that inhibits a particular class of enzymes that they believed could include the candidate molecule that acted on CatSper. The hunch proved correct: the treated cells remained inactive after progesterone exposure, indicating that CatSper was not directly involved.

Working with modified progesterone, the researchers eventually isolated ABHD2 from the sperm tails. When the researchers inactivated ABHD2, exposure to progesterone failed to activate the sperm cells, confirming that ABHD2 is the molecular target for progesterone.

All of the technical terminology aside, this means that the researchers have pinned down the cellular switch that boosts the sperm along to the egg, so by blocking the ABHD2 activity, new male birth control methods could be on the way. Conversely, enhancing the enzyme could lead to new treatments for male infertility.

It will be interesting to see how this discovery impacts future research concerning male birth control and infertility treatments. Perhaps it’s the missing piece of information that will quickly yield an effective new male contraception option.

 

SOURCES

http://www.nih.gov/news-events/news-releases/researchers-identify-molecule-needed-sperm-activation

http://www.ncbi.nlm.nih.gov/pubmed/26989199

http://thescienceexplorer.com/brain-and-body/nih-funded-study-made-breakthrough-discovery-could-lead-new-male-birth-control

http://www.jhunewsletter.com/2016/03/31/researchers-find-a-protein-fertilization-catalyst/

 

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Genes involved in Male Fertility and Sperm-egg Binding

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Biology & Bio Instrumentation, tagged , , , , , , , , , on October 8, 2012| 3 Comments »

 

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

An estimated 10 to 15% of couples suffer from infertility, and many treatment decisions rely on trial and error. A team of international scientists has found a common genetic variant which may explain why some men with normal sperm counts and good quality sperm are affected by infertility.

The study findings suggested that men with a variation in a gene which codes for a sperm-coating protein called beta defensin 126 (DEFB126) have a reduction in the protein coat on the outside of the sperm which makes it difficult for the sperm to ‘swim’ to the egg.

Dr Edward Hollox of the University of Leicester and co-author of the study said: ‘If you’ve got this gene variant you should allow that little bit longer if your partner’s planning to get pregnant’. The researchers, including scientists from the University of California and the Anhui Medical University in China, carried out the study on over 500 newly-wed Chinese couples who were trying for a baby.

They found that when men’s sperm lacked a coat of the DEFB126 protein, their wives were significantly less likely than expected to become pregnant.

Previous studies have shown that two copies of the genetic variant may be found in up to one quarter of men around the world, with about half of all men having one copy. The DEFB126 protein coat helps sperm to swim through cervical mucus and evade the woman’s immune system, as well as enabling it to attach to the walls of fallopian tubes.

The study showed, however, that men with two copies of the variant produced sperm that were less able to swim through a substitute to cervical mucus, hyaluronic acid gel. In macaques, it has already been shown that this protein is important in evading the immune system and the researchers believe the protein coat plays the same role in humans. Commenting on the study, Dr Allan Pacey, senior lecturer in Andrology at the University of Sheffield, said: ‘We actually understand very little about the subtle molecular events which occur in sperm as they make their journey through the woman’s body to fertilise an egg’. The research was published in the journal Science Translational Medicine. If replicated in future studies, these findings promise to guide choices about the timing and type of assisted reproduction interventions—and further hint at the possibility of treating sperm from del/del homozygotes to promote fertility.

A gene which helps sperm bind to an egg has been identified by scientists. Sperm-to-egg binding is an essential process during fertilization and although the preliminary studies were performed on mice, the gene may represent a new target for infertility treatments. Sperm from mice that had the gene switched off were only able to fertilise eggs from female mice three percent of the time compared to 80 percent fertilisation success in normal mice.

The gene codes for a protein called PDILT which helps another gene product to form and assemble correctly and then to reach the surface of a sperm. Once this happens the sperm is able to navigate the uterus and oviduct and penetrate the sticky outer layers of an egg. The study, which is published in PNAS (Proceedings of the National Academy of Sciences), also demonstrates the importance of cumulus cells, a cluster of cells that surround and protect the egg, as their presence allows sperm to bind to their target. Sperm from mice that had their PDILT gene switched off would not bind to a bare egg, but would bind to an egg surrounded by cumulus cells.

Co-author Dr Adam Benham from Durham University in the UK said that the PDILT protein is ‘an essential part of the navigation system of sperm. Like any navigation system, you have to programme where it is that you want to go and this protein plays an essential role in getting sperm to the right destination, in good shape, and in good time’. A question now for the scientists is whether the PDILT gene has as much importance in human fertility as it does in mice. ‘Mutations in the gene may be responsible for unexplained male fertility problems and further research may aid more effective IVF treatment‘, said Dr Benham.

Source References:

http://stm.sciencemag.org/content/3/92/92ps31.abstract

http://www.bionews.org.uk/page_142955.asp

http://www.itv.com/news/update/2012-05-01/scientists-discover-new-gene-key-to-fertility/

http://www.bionews.org.uk/page_102705.asp

 

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Innovations in Bio instrumentation in Reproductive Clinical and Male Fertility Labs in the US

Posted in Reproductive Biology & Bio Instrumentation, tagged , , , , , on July 1, 2012| 5 Comments »

Reporter: Sudipta Saha, Ph.D.

Laboratory testing is an integral component of the evaluation of the infertile men. This testing must be appropriate and specific for the individual couple. As there are many tests that evaluate various aspects of infertility, the urologist have to decide what information the tests can offer as well as the limitations of each assay. The semen analysis remains the cornerstone of the evaluation but is not a functional assay. Other assays such as sperm-cervical mucus tests, hemizona assays, and the sperm-penetration assay are functional tests. Through the appropriate use of these and other tests, the urologist will be capable of better and more accurately counseling the infertile couple (http://www.springerlink.com/content/t518435632851834/).

5.3 million American couples of reproductive age (9%) are affected by infertility, among which male factors account for up to 50% of cases, which necessitates the identification of parameters defining sperm quality, including sperm count and motility. In vitro fertilization (IVF) with or without intra cytoplasmic sperm injection (ICSI) has become the most widely used assisted reproductive technology (ART) in modern clinical practice to overcome male infertility challenges. One of the obstacles of IVF and ICSI lies in identifying and isolating the most motile and presumably healthiest sperm from semen samples that have low sperm counts (oligozoospermia) and/or low sperm motility (oligospermaesthenia). Microfluidic systems have shown potential to sort sperm with flow systems. However, the small field of view (FOV) of conventional microscopes commonly used to image sperm motion presents challenges in tracking a large number of sperm cells simultaneously. To address this challenge, Zhang et. al. at Harvard Medical School and MIT integrated a lensless charge-coupled device (CCD) with a microfluidic chip to enable wide FOV and automatic recording as the sperm move inside a microfluidic channel. The integrated system enables the sorting and tracking of a population of sperm that have been placed in a microfluidic channel. This channel can be monitored in both horizontal and vertical configuration similar to a swim up column method used clinically. Sperm motilities can be quantified by tracing the shadow paths for individual sperm. Moreover, as the sperm are sorted by swimming from the inlet towards the outlet of a microfluidic channel, motile sperm that reach the outlet can be extracted from the channel at the end of the process. This technology can lead to methods to evaluate each sperm individually in terms of motility response in a wide field of view, which could prove especially useful, when working with oligozoospermic or oligospermaesthenic samples, in which the most motile sperm need to be isolated from a pool of small number of sperm (http://mit.edu/bammlabs/Lensless_Imaging.pdf).

There are also some new kit based methods developed to analyze male fertility at home. There is no need to count hundreds of sperm in these methods. They are user-friendly, quite affordable (between 40 and 100 dollars) and quick. One of the pioneers on the market is FertilMARQ Home Diagnostic Screening Test, which works by staining the cells in the sperm sample to produce a color. The intensity of this color is then compared to a color reference on the FertilMARQ test cassette providing results with an overall accuracy of 78 percent. Another popular home kit is Spermcheck fertility, known to be 97 percent accurate. This test is based on the detection of SP-10, a protein compound found on the surface of the head of a sperm cell and which concentrations are directly related to the sperm count number (http://howto.wired.com/wiki/Check_a_Man’s_Sperm_Count).

Techniques such as Vasectomy Reversal and Tubal Ligation Reversal, In vitro fertilization (IVF), Intra-cytoplasmic sperm injection (ICSI) have also improved with respect to the instrumentation used. Dr. Sherman J. Silber, M.D. and his Japanese collaborators have recently developed a new “mini-IVF” technique that saves money, eliminates complications of IVF, and is useful for older women and women with low ovarian reserve. (http://www.infertile.com/).

The pioneer company in making the most sophisticated and most popular sperm analysis instrument is Hamilton Thorne (http://www.hamiltonthorne.com/products/casa/systems-index.htm) and their website may be reviewed for more knowledge on modern sperm analysis.

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