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Archive for the ‘Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics’ Category


Changes in Levels of Sex Hormones and N-Terminal Pro–B-Type Natriuretic Peptide as Biomarker for Cardiovascular Diseases

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

 

Considerable differences exist in the prevalence and manifestation of atherosclerotic cardiovascular disease (CVD) and heart failure (HF) between men and women. Premenopausal women have a lower risk of CVD and HF compared with men; however, this risk increases after menopause. Sex hormones, particularly androgens, are associated with CVD risk factors and events and have been postulated to mediate the observed sex differences in CVD.

 

B-type natriuretic peptides (BNPs) are secreted from cardiomyocytes in response to myocardial wall stress. BNP plays an important role in cardiovascular remodelling and volume homeostasis. It exerts numerous cardioprotective effects by promoting vasodilation, natriuresis, and ventricular relaxation and by antagonizing fibrosis and the effects of the renin-angiotensin-aldosterone system. Although the physiological role of BNP is cardioprotective, pathologically elevated N-terminal pro–BNP (NT-proBNP) levels are used clinically to indicate left ventricular hypertrophy, dysfunction, and myocardial ischemia. Higher NT-proBNP levels among individuals free of clinical CVD are associated with an increased risk of incident CVD, HF, and cardiovascular mortality.

 

BNP and NT-proBNP levels are higher in women than men in the general population. Several studies have proposed the use of sex- and age-specific reference ranges for BNP and NT-proBNP levels, in which reference limits are higher for women and older individuals. The etiology behind this sex difference has not been fully elucidated, but prior studies have demonstrated an association between sex hormones and NT-proBNP levels. Recent studies measuring endogenous sex hormones have suggested that androgens may play a larger role in BNP regulation by inhibiting its production.

 

Data were collected from a large, multiethnic community-based cohort of individuals free of CVD and HF at baseline to analyze both the cross-sectional and longitudinal associations between sex hormones [total testosterone (T), bioavailable T, freeT, dehydroepiandrosterone (DHEA), SHBG, and estradiol] and NT-proBNP, separately for women and men. It was found that a more androgenic pattern of sex hormones was independently associated with lower NT-proBNP levels in cross-sectional analyses in men and postmenopausal women.

 

This association may help explain sex differences in the distribution of NT-proBNP and may contribute to the NP deficiency in men relative to women. In longitudinal analyses, a more androgenic pattern of sex hormones was associated with a greater increase in NT-proBNP levels in both sexes, with a more robust association among women. This relationship may reflect a mechanism for the increased risk of CVD and HF seen in women after menopause.

 

Additional research is needed to further explore whether longitudinal changes in NT-proBNP levels seen in our study are correlated with longitudinal changes in sex hormones. The impact of menopause on changes in NT-proBNP levels over time should also be explored. Furthermore, future studies should aim to determine whether sex hormones directly play a role in biological pathways of BNP synthesis and clearance in a causal fashion. Lastly, the dual role of NTproBNP as both

  • a cardioprotective hormone and
  • a biomarker of CVD and HF, as well as
  • the role of sex hormones in delineating these processes,

should be further explored. This would provide a step toward improved clinical CVD risk stratification and prognostication based on

  • sex hormone and
  • NT-proBNP levels.

 

References:

 

https://www.medpagetoday.com/clinical-connection/cardio-endo/76480?xid=NL_CardioEndoConnection_2018-12-27

 

https://www.ncbi.nlm.nih.gov/pubmed/30137406

 

https://www.ncbi.nlm.nih.gov/pubmed/22064958

 

https://www.ncbi.nlm.nih.gov/pubmed/24036936

 

https://www.ncbi.nlm.nih.gov/pubmed/19854731

 

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

 

Over the past 20 years, studies have shown that girls and possibly boys have been experiencing puberty at progressively younger ages. This is troubling news, as earlier age at puberty has been linked with increased risk of mental illness, breast and ovarian cancer in girls and testicular cancer in boys. Researchers found that daughters of mothers who had higher levels of diethyl phthalate and triclosan in their bodies during pregnancy experienced puberty at younger ages. The same trend was not observed in boys. So, researchers suspected that girls exposed to chemicals commonly found in toothpaste, makeup, soap and other personal care products before birth may hit puberty earlier.

 

Diethyl phthalate is often used as a stabilizer in fragrances and cosmetics. The antimicrobial agent triclosan — which the FDA banned from use in hand soap in 2017 because it was shown to be ineffective — is still used in some toothpastes. Researchers suspected that many chemicals in personal care products can interfere with natural hormones in human bodies, and studies have shown that exposure to these chemicals can alter reproductive development in rats. Chemicals that have been implicated include phthalates, which are often found in scented products like perfumes, soaps and shampoos; parabens, which are used as preservatives in cosmetics; and phenols, which include triclosan.

 

However, few studies have looked at how these chemicals might affect the growth of human children. This present study at UC Berkeley, USA recruited pregnant women living in the farm-working, primarily Latino communities of Central California’s Salinas Valley between 1999 and 2000. While the primary aim of the study was to examine the impact of pesticide exposure on childhood development, the researchers used the opportunity to examine the effects of other chemicals as well. The scientists measured concentrations of phthalates, parabens and phenols in urine samples taken from mothers twice during pregnancy, and from children at the age of 9. They then followed the growth of the children — 159 boys and 179 girls — between the ages of 9 and 13 to track the timing of developmental milestones marking different stages of puberty.

 

The vast majority — more than 90 percent — of urine samples of both mothers and children showed detectable concentrations of all three classes of chemicals, with the exception of triclosan which was present in approximately 70 percent of samples. The researchers found that every time the concentrations of diethyl phthalate and triclosan in the mother’s urine doubled, the timing of developmental milestones in girls shifted approximately one month earlier. Girls who had higher concentrations of parabens in their urine at age 9 also experienced puberty at younger ages. However, it is unclear if the chemicals were causing the shift, or if girls who reached puberty earlier were more likely to start using personal care products at younger ages.

 

The limitations are that these chemicals are quickly metabolized and one to two urinary measurements per developmental point may not accurately reflect usual exposure. The study population was limited to Latino children of low socioeconomic status living in a farmworker community and may not be widely generalizable. But, this study contributes to a growing literature that suggests that exposure to certain endocrine disrupting chemicals may impact timing of puberty in children.

 

References:

 

https://www.universityofcalifornia.edu/news/prenatal-exposure-chemicals-personal-care-products-may-speed-puberty-girls?utm_source=fiat-lux

 

https://www.ncbi.nlm.nih.gov/pubmed/30517665

 

https://www.ncbi.nlm.nih.gov/pubmed/24781428

 

https://www.ncbi.nlm.nih.gov/pubmed/30203993

 

https://www.ncbi.nlm.nih.gov/pubmed/25173057

 

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Micronutrients, Macronutrients and Dietary Patterns: Nutrition and Fertility

Reporter: Aviva Lev-Ari, PhD, RN

Folic acid. Folic acid is important for germ cell production and pregnancy. The recommended daily dose to prevent neural tube defects is 400-800 µg. Women who take folic acid-containing multivitamins are less likely to be anovulatory, and the time to achieve a pregnancy is reduced. Those who consume more than 800 µg of folic acid daily are more likely to conceive with assisted reproductive technology (ART) than those whose daily intake is less than 400 µg.

Vitamin D. Vitamin D may affect fertility through receptors found in the ovaries and endometrium. An extremely low vitamin D level (< 20 ng/mL) is associated with higher risk for spontaneous miscarriage risk. Some reports suggest that women with adequate vitamin D levels (> 30 ng/mL) are more likely to conceive after ART when compared with those whose vitamin D levels are insufficient (20-30 ng/mL), or deficient (< 20 ng/mL). These findings, however, are inconclusive.

Carbohydrates. Dietary carbohydrates affect glucose homeostasis and insulin sensitivity, and by these mechanisms can affect reproduction. The impact is most pronounced among women with polycystic ovary syndrome (PCOS). In women with PCOS, a reduction in glycemic load improves insulin sensitivity as well as ovulatory function. Whole grains have antioxidant effects and also improve insulin sensitivity, thereby positively influencing reproduction.

Omega-3 supplements. Omega-3 polyunsaturated fatty acids lower the risk for endometriosis. Increased levels of omega-3 polyunsaturated fatty acids are associated with higher clinical pregnancy and live birth rates.

Protein and dairy. Some reports suggest that dairy protein intake lowers ovarian reserve. Other reports suggest improved ART outcomes with increased dairy intake. Meat, fish, and dairy products, however, can also serve as vehicles for environmental contamination that may adversely affect the embryo. Fish, on the other hand, has been shown to exert positive effects on fertility.

Dietary approach. In general, a Mediterranean diet is favored (high intake of fruits, vegetables, fish, chicken, and olive oil) among women diagnosed with infertility.

Recommendations

A well-balanced diet, rich in vegetables and fruits, is preferred for infertile women and should provide the required micro- and macronutrients. It remains common for patients consume a wide variety of vitamin, mineral, and micronutrient supplements daily.[4] Supplements should not replace food sources of vitamins and trace elements because of differences in bioavailability (natural versus synthetic), and inaccuracy of label declarations may result in suboptimal intake of important nutrients.[5,6] Furthermore, naturally occurring vitamins and micronutrients are more efficiently absorbed.

With respect to overall diet, women are advised to follow a caloric intake that won’t contribute to being overweight or obese. Obesity is on the rise among younger people, including children. Obese women have a lower chance of conceiving and are less likely to have an uncomplicated pregnancy.[7] Proper weight can be maintained with an appropriate diet and regular exercise.

Finally, women must abstain from substances that are potentially harmful to pregnancy (eg, smoking, alcohol, recreational drugs, high caffeine intake).

Causes of Infertility

  • ovulatory defect,
  • tubal occlusion,
  • low sperm counts), and many

Factors lower the chance of pregnancy

  • older age,
  • lower ovarian reserve,
  • endometriosis

Factors can’t be altered

  • age and
  • ovarian reserve

Modifiable Factors:

  • body weight and
  • lifestyle habits

 

REFERENCES

SOURCE

http://Peter Kovacs. Food and Fertility: What Should Women Consume When Trying to Conceive? – Medscape – Dec 06, 2018.

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

 

Long interspersed nuclear elements 1 (LINE1) is repeated half a million times in the human genome, making up nearly a fifth of the DNA in every cell. But nobody cared to study it and may be the reason to call it junk DNA. LINE1, like other transposons (or “jumping genes”), has the unusual ability to copy and insert itself in random places in the genome. Many other research groups uncovered possible roles in early mouse embryos and in brain cells. But nobody quite established a proper report about the functions of LINE1.

 

Geneticists gave attention to LINE1 when it was found to cause cancer or genetic disorders like hemophilia. But researchers at University of California at San Francisco suspected there was more characteristics of LINE1. They suspected that if it can be most harmless then it can be worst harmful also.

 

Many reports showed that LINE1 is especially active inside developing embryos, which suggests that the segment actually plays a key role in coordinating the development of cells in an embryo. Researchers at University of California at San Francisco figured out how to turn LINE1 off in mouse embryos by blocking LINE1 RNA. As a result the embryos got stuck in the two-cell stage, right after a fertilized egg has first split. Without LINE1, embryos essentially stopped developing.

 

The researchers thought that LINE1 RNA particles act as molecular “glue,” bringing together a suite of molecules that switch off the two-cell stage and kick it into the next phase of development. In particular, it turns off a gene called Dux, which is active in the two-cell stage.

 

LINE1’s ability to copy itself, however, seems to have nothing to do with its role in embryonic development. When LINE1 was blocked from inserting itself into the genome, the embryonic stem cells remained unaffected. It’s possible that cells in embryos have a way of making LINE1 RNA while also preventing its potentially harmful “jumping” around in the genome. But it’s unlikely that every one of the thousands of copies of LINE1 is actually being used to regulate embryonic development.

 

LINE1 is abundant in the genomes of almost all mammals. Other transposons, also once considered junk DNA, have turned out to have critical roles in development in human cells too. There are differences between mice and humans, so, the next obvious step is to study LINE1 in human cells, where it makes up 17 percent of the genome.

 

References:

 

https://www-theatlantic-com.cdn.ampproject.org/c/s/www.theatlantic.com/amp/article/563354/

 

https://www.ncbi.nlm.nih.gov/pubmed/29937225

 

https://www.nature.com/scitable/topicpage/transposons-the-jumping-genes-518

 

https://www.sciencedaily.com/releases/2018/06/180621141038.htm

 

https://www.ncbi.nlm.nih.gov/pubmed/16015595

 

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

 

Hepatitis B virus can cause serious, long-term health problems, such as liver disease and cancer, and can spread from mother-to-child during delivery. According to the latest estimates from the World Health Organization (WHO), approximately 257 million people in 2015 were living with the virus. Countries in Asia have a high burden of hepatitis B. There is no cure, and antiviral drugs used to treat the infection usually need to be taken for life.

 

To prevent infection, WHO recommends that all newborns receive their first dose of hepatitis B vaccine within 24 hours of delivery. Infants born to hepatitis B-infected mothers are also given protective antibodies called hepatitis B immune globulin (HBIG). However, mother-to-child transmission can still occur in women with high levels of virus in their blood, as well as those with mutated versions of the virus.

 

Tenofovir disoproxil fumarate (TDF), an antiviral drug commonly prescribed to treat hepatitis B infection, does not significantly reduce mother-to-child transmission of hepatitis B virus when taken during pregnancy and after delivery, according to a phase III clinical trial in Thailand funded by the National Institutes of Health. The study tested TDF therapy in addition to the standard preventative regimen — administration of hepatitis B vaccine and protective antibodies at birth — to explore the drug’s potential effects on mother-to-child transmission rates. The results appear in the New England Journal of Medicine.

 

The present study was conducted at 17 hospitals of the Ministry of Public Health in Thailand. It screened more than 2,500 women for eligibility and enrolled 331 pregnant women with hepatitis B. The women received placebo (163) or TDF (168) at intervals from 28 weeks of pregnancy to two months after delivery. All infants received standard hepatitis B preventatives given in Thailand, which include HBIG at birth and five doses of the hepatitis B vaccine by age 6 months (which differs from the three doses given in the United States). A total of 294 infants (147 in each group) were followed through age 6 months.

 

Three infants in the placebo group had hepatitis B infection at age 6 months, compared to zero infants in the TDF treatment group. Given the unexpectedly low transmission rate in the placebo group, the researchers concluded that the addition of TDF to current recommendations did not significantly reduce mother-to-child transmission of the virus.

 

According to the study, the clinical trial had enough participants to detect statistical differences if the transmission rate in the placebo group reached at least 12 percent, a rate observed in previous studies. Though the reasons are unknown, the researchers speculate that the lower transmission rate seen in the study may relate to the number of doses of hepatitis B vaccine given to infants in Thailand, lower rates of amniocentesis and Cesarean section deliveries in this study, or the lower prevalence of mutated viruses that result in higher vaccine efficacy in Thailand compared to other countries.

 

References:

 

https://www.nih.gov/news-events/news-releases/antiviral-drug-not-beneficial-reducing-mother-child-transmission-hepatitis-b-when-added-existing-preventatives

 

https://www.ncbi.nlm.nih.gov/pubmed/29514030

 

https://www.ncbi.nlm.nih.gov/pubmed/29514035

 

https://www.ncbi.nlm.nih.gov/pubmed/25240752

 

https://www.ncbi.nlm.nih.gov/pubmed/28188612

 

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

 

Biologists may have been building a more nuanced view of sex, but society has yet to catch up. True, more than half a century of activism from members of the lesbian, gay, bisexual and transgender community has softened social attitudes to sexual orientation and gender. Many societies are now comfortable with men and women crossing conventional societal boundaries in their choice of appearance, career and sexual partner. But when it comes to sex, there is still intense social pressure to conform to the binary model.

 

This pressure has meant that people born with clear DSDs (difference/disorder of sex development) often undergo surgery to ‘normalize’ their genitals. Such surgery is controversial because it is usually performed on babies, who are too young to consent, and risks assigning a sex at odds with the child’s ultimate gender identity — their sense of their own gender. Intersex advocacy groups have therefore argued that doctors and parents should at least wait until a child is old enough to communicate their gender identity, which typically manifests around the age of three, or old enough to decide whether they want surgery at all.

 

As many as 1 person in 100 has some form of “DSD” with or without external manifestation. Diagnoses of DSDs previously relied on hormone tests, anatomical inspections and imaging, followed by painstaking tests of one gene at a time. Now, advances in genetic techniques mean that teams can analyze multiple genes at once, aiming straight for a genetic diagnosis and making the process less stressful for families. Children with DSDs are treated by multidisciplinary teams that aim to tailor management and support to each individual and their family, but this usually involves raising a child as male or female even if no surgery is done.

 

The simple scenario that all learn is that two X chromosomes make someone female, and an X and a Y chromosome make someone male. These are simplistic ways of thinking about what is scientifically very complex. Anatomy, hormones, cells, and chromosomes (and also personal identity convictions) are actually not usually aligned with this binary classification.

 

More than 25 genes that affect sex development have now been identified, and they have a wide range of variations that affect people in subtle ways. Many differences aren’t even noticed until incidental medical encounters, such as a forty-six-year-old woman pregnant with her third child, found after amniocentesis that half her cells carry male chromosomes. Or a seventy-year-old father of three who learns during a hernia repair that he has a uterus.

 

Furthermore, scientists now understood that everyone’s body is made up of a patchwork of genetically distinct cells, some of which may have a different sex than the rest. This “mosaicism” can have effects ranging from undetectable to extraordinary, such as “identical” twins of different sexes. An extremely common instance of mosaicism comes from cells passing over the placental barrier during pregnancy. Men often carry female cells from their mothers, and women carry male cells from their sons. Research has shown that these cells remain present for decades, but what effects they have on disease and behavior is an essentially unstudied question.

 

References:

 

https://www.theguardian.com/science/2017/mar/02/cambridge-scientists-create-first-self-developing-embryo-from-stem-cells

 

https://www.ncbi.nlm.nih.gov/pubmed/25693544

 

http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.34123/abstract;jsessionid=A330AD995EE25C7A0AD5EA478694ADD8.f04t01

 

https://www.ncbi.nlm.nih.gov/pubmed/25091731

 

https://www.ncbi.nlm.nih.gov/pubmed/1695712

 

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

 

During menopause a woman’s ovaries stop working—leading to hot flashes, sleep problems, weight gain, and worse, bone deterioration. Now scientists are exploring whether transplanting lab-made ovaries might stop those symptoms. In one of the first efforts to explore the potential of such a technique, researchers say they used tissue engineering to construct artificial rat ovaries able to supply female hormones like estrogen and progesterone. A research carried out at Wake Forest Baptist Medical Center, suggests a potential alternative to the synthetic hormones millions of women take after reaching middle age. A paper describing the findings was published in Nature Communications.

 

Women going through menopause, as well as those who have undergone cancer treatment or had their ovaries removed for medical purposes, lose the ability to produce important hormones, including estrogen and progesterone. Lower levels of these hormones can affect a number of different body functions. To counteract unpleasant symptoms, many women turn to combinations of hormone replacement medications—synthetic estrogen and progestin. Pharmacologic hormone replacement therapy (pHRT) with estrogen alone or estrogen and progestogens is known to effectively ameliorate the unpleasant symptoms. But hormone replacement carries an increased risk of heart disease and breast cancer, so it’s not recommended for long-term use. In these circumstances artificial ovaries could be safer and more effective.

 

Regenerative medicine approaches that use cell-based hormone replacement therapy (cHRT) offer a potential solution to temporal control of hormone delivery and the ability to restore the HPO (Hypothalamo-Pituitary-Ovarian) axis in a way not possible with pHRT. Scientists have previously described an approach to achieve microencapsulation of ovarian cells that results in bioengineered constructs that replicate key structure-function relationships of ovarian follicles as an approach to cHRT. In the present study the scientists have adapted an isogeneic cell-based construct to provide a proof-of-concept for the potential benefits of cHRT.

 

Tissue or cell encapsulation may offer effective strategies to fabricate ovarian constructs for the purpose of fertility and/or hormone replacement. Approaches using segmental ovarian tissue or whole-follicle implantation (typically with a focus on cryopreservation of the tissue for reproductive purposes) have resulted in detectable hormone levels in the blood after transplantation. Previous studies have also shown that autotransplantation of frozen-thawed ovarian tissue can lead to hormone secretion for over 5 years in humans.

 

Although these approaches can be used to achieve the dual purpose of fertility and hormone replacement in premenopausal women undergoing premature ovarian failure, they would have limited application in postmenopausal women who only need hormone replacement to manage menopausal symptoms and in whom fertility is not desirable. In full development, the technology described in this research is focused on hormone replacement, would meet the needs of the latter group of women that is the postmenopausal women.

 

The cell-based system of hormone replacement described in this report offers an attractive alternative to traditional pharmacological approaches and is consistent with current guidelines in the U.S. and Europe recommending the lowest possible doses of hormone for replacement therapy. In the present research sustained stable hormone release over the course of 90 days of study was demonstrated. The study also demonstrated the effective end-organ outcomes in body fat composition, uterine health, and bone health. However, additional studies will be required to determine the sustainability of the hormone secretion of the constructs by measuring hormone levels from implanted constructs for periods longer than 3 months in the rat model.

 

This study highlights the potential utility of cHRT for the treatment and study of conditions associated with functional loss of the ovaries. Although longer-term studies would be of future interest, the 90-day duration of this rodent model study is consistent with others investigating osteoporosis in an ovariectomy model. However, this study provides a proof-of-concept for cHRT, it suffers the limitation that it is only an isogeneic-based construct implantation. Scientists think that further studies in either allogeneic or xenogeneic settings would be required with the construct design described in this report in the path towards clinical translation given that patients who would receive this type of treatment are unlikely to have sufficient autologous ovarian cells for transplantation.

 

Researchers from Copenhagen, Denmark, were recently able to isolate viable, early stage follicles in ovarian tissue. They have successfully stripped ovarian tissue from its cancerous cells and used the remaining scaffold to support the growth and survival of human follicles. This “artificial ovary” may help y to help women who have become infertile due to cancer and chemotherapy. But, the research is presently at a very preliminary stage and much research is still required to ensure that cancer cells are not reintroduced during the grafting process.

 

References:

 

https://www.technologyreview.com/the-download/609677/will-artificial-ovaries-mean-no-more-menopause/

 

https://www.nature.com/articles/s41467-017-01851-3

 

https://www.ncbi.nlm.nih.gov/pubmed/23274068

 

https://www.ncbi.nlm.nih.gov/pubmed/26210678

 

https://www.ncbi.nlm.nih.gov/pubmed/21954279

 

http://www.frontlinegenomics.com/news/24423/artificial-ovaries-hope-to-help-infertile-women-conceive-following-chemotherapy/

 

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