Category: Gender

Categories : Gender Mental HealthTags :

Researchers Tie Sex-specific Genes to Depression

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Depression is widely reported to be more common in women than in men, with women twice as likely to receive a diagnosis than men. A new study published in Nature has found that there are differences between male and female genes and how they relate to depression.

In a genome-wide association(GWA} study, the McGill University researchers analysed the genomes of more than 270 000 individuals. They found that sex-specific prediction methods were more accurate in forecasting an individual’s genetic risk of developing depression than prediction methods that did not specify sex. The researchers found 11 areas of DNA that were linked to depression in females, and only one area in males.

In both males and females, genetic correlations were significant between the broad depression GWA and other psychopathologies; however, correlations with educational attainment and metabolic features including body fat, waist circumference, waist-to-hip ratio and triglycerides were significant only in females. Gene-based analysis showed 147 genes significantly associated with broad depression in the total sample, 64 in the females and 53 in the males.

Despite the biological processes involved in depression being similar in males and females, researchers found that different genes were involved for each sex. This information can be useful to identify future sex-specific treatments for depression.  “This is the first study to describe sex-specific genetic variants associated with depression, which is a very prevalent disease in both males and females. These findings are important to inform the development of specific therapies that will benefit both men and women while accounting for their differences,” says Dr Patricia Pelufo Silveira, lead author and Associate Professor in the Department of Psychiatry. “In the clinic, the presentation of depression is very different for men and women, as well as their response to treatment, but we have very little understanding of why this happens at the moment.”

Source: McGill University

Categories : Gender Medical Research & TechnologyTags :

Study Reveals How Androgen Receptor Functions are Affected by Mutations

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Testosterone molecule
Model of a testosterone molecule. Source: Wikimedia CC0

The androgen receptor is a key transcriptional factor for proper sex development, especially in males and the physiological balance of all the tissues that express this receptor. The androgen receptor is involved in several pathologies and syndromes, such as spinal and bulbar muscular atrophy or androgen insensitivity syndrome, for which there is no specific treatment. Regarded as the main initial and progression factor in prostate cancer, this receptor has been the main therapeutic target for the treatment against this disease for decades.

Now, a study published in Science Advances describes the structural and functional effects of mutations on the androgen receptor, as well as how these changes lead to the development of prostate cancer.

Point mutations in the androgen receptor

The human androgen receptor is a key protein in the development and functioning of the prostate in response to male hormones, such as testosterone. Point mutations in the androgen receptor – specifically, one amino acid swapped for another – are one of the main mechanisms than can lead to structural and functional alterations in the receptor, which result in the development of diseases.

The results of the University of Barcelona-led study show that the analysed mutations affect several functional regions of the union domain of the androgen receptor to testosterone. In particular, these are mutations that alter a region of the receptor which is the target for posttranscriptional modifications (that is, modifications in the protein once this is produced).

This type of chemical alterations affect specific amino acids of the androgen receptor and are executed by regulating proteins which are critical for the proper functioning of the receptor. If this receptor’s regulation pathway is altered, such as the case of the presence of mutations described by the team, its function is deregulated and it can be dysfunctional and cause pathologies.

“In our study, we experimentally checked that these mutations deregulate a specific mutation, known as arginine methylation, which is one of the posttranscriptional modifications, due to the structural changes these alterations produce in a functional area of the receptor. Also, we could observe that the deregulation of the androgen receptor methylation involves relevant changes in its function within the cell,” the team concludes.

Source: University of Barcelona

Categories : Cardiovascular Disease Exercise GenderTags :

Strenuous Jobs Increase Men’s Cardiovascular Risk, but Reduce Women’s

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A long-term Danish study found that high physical activity at work was associated with higher risk of ischaemic heart disease (IHD) in men, but in women, this was associated with lower risk. The findings, published in the European Journal of Preventive Cardiology, highlight the importance of taking gender into account when considering the impact of high levels of occupational physical activity (OPA).

While previous studies have shown that physical activities in leisure time are protective against cardiovascular disease, high levels of OPA were shown to have no benefit – or even a detrimental effect.

The study followed up participants aged 30–61 years old after 34 years who took part in the Danish Monica 1 study in 1982–84. Participants, 1399 women and 1706 men, were actively employed, without prior IHD and who answered a question on OPA. The participants’ medical records were located in the Danish National Patient Registry and the researchers analysed the data, controlling for increasing numbers of factors such as age, then age and sex, and then age and sex plus factors such as smoking.

Compared to women doing sedentary work, women in all other OPA categories had a lower hazard ratio (HR) for IHD. Among men, the risk of IHD was 22% higher among those with light OPA, and 42% and 46% higher among those with moderate OPA with some lifting or strenuous work with heavy lifting, respectively, compared to men with sedentary OPA. Compared to women with sedentary work, HR for IHD was higher among men in all OPA categories, and a statistically significant interaction between OPA and sex was found.

Demanding or strenuous OPA seems to be a risk factor for IHD among men, whereas a higher level of OPA seems to protect from IHD among women. The researchers wrote that this underlines the importance of taking into account sex differences in studies of health effects of OPA. Future studies should investigate the underlying mechanisms for this difference, such as differences in exposure and physiology.

Categories : Cancer GenderTags :

In Women, Certain Immune Cell Hinders Pancreatic Cancer Immunotherapy

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Photo by Tima Miroshnichenko on Pexels

Immunotherapy has limited effect for pancreatic cancer, and differs between men and women. A new study published in Cancer Research reveals certain immune cells in women with pancreatic cancer that, instead of fighting the tumour, interferes with the body’s immune response. These findings may pave the way for a more sex-specific treatment.

“More and more evidence is coming in that male and female hormones affect our immune system, but much remains to be done before sex can be included as a self-evident biological factor in medical research and therapy,” says the paper’s first author Fei He, former visiting researcher at Karolinska Institutet. “Our results provide new perspectives that can have high impact on the treatment of cancer.”

In recent years, immunotherapy, which stimulates the immune system to attack cancer cells, has contributed significantly to the treatment of different kinds of cancer, such as melanoma and lung, kidney and liver cancer. However, it is much less effective against pancreatic cancer, which remains one of the deadliest kinds of cancer that leaves patients, on average, with four to six months left to live after diagnosis.

Sex-biased differences in the immune response

Previous studies have shown that there are sex-bound biological differences in the male and female immune system that, amongst other effects, determine how tumours grow and the body’s ability to defend itself against them. The present study addressed what might cause such sex-related disparities in the immune response to pancreatic cancer.

The study revealed the presence of a subpopulation of myeloid cells in women that protect the tumour and prevents the immune system’s T cells from infiltrating the tumour and attacking the cancer cells.

“This sub-group of immune cells correlates with poor survival exclusively in female cancer patients,” says the study’s corresponding author and principal investigator Dhifaf Sarhan, assistant professor at the Department of Laboratory Medicine, Karolinska Institutet. “Our results show that the immune cells express a specific protein called FPR2 and can serve both as a sex-specific prognostic factor and a therapeutic target.”

New target for immunotherapy in women

The results can be useful to the development of diagnostic tools and immunotherapy for pancreatic cancer that take into account biological differences between men and women. The study used a combination of methods including single-cell RNA sequencing, proteomics, test tube and patient validation, and treatments of 3D pancreatic cancer models and mice.

“The next step is to follow up our new immunotherapy target for women,” says Dr Sarhan. “We’re also performing extensive analyses to understand how immunological sex differences drive tumour development in different ways in male and female cancer patients with the goal to find and develop immunotherapy targets for each group.”

Source: Karolinska Institutet

Categories : Cardiovascular Disease GenderTags :

Gender Affirming Hormone Therapy Linked to Greatly Increased Cardiovascular Risk

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Source: CC0

People undergoing hormone replacement therapy (HRT) for gender dysphoria have a greatly increased risk of serious cardiac events, according to a study presented at the American College of Cardiology annual meeting. Compared to people with gender dysphoria not taking HRT, those taking HRTY saw a seven-fold risk increase for ischaemic stroke, and risk increases for myocardial infarction and pulmonary embolism.

People with gender dysphoria may use HRT as part of gender affirmation therapy to transition to a different gender than their biological sex at birth. HRT for this purpose is rapidly increasing, especially among teens and young adults.

Previous research on hormone-modulating medications has primarily focused on younger women using hormone-based birth control or on older women following a hysterectomy or during menopause. In these populations, long-term HRT has been associated with an increased risk of breast cancer, stroke and blood clots.

Researchers retrospectively examined rates of cardiovascular events in over 21 000 people with gender dysphoria from a national database of hospital records, of whom 1675 had used HRT. Typically, people assigned male at birth receive oestrogen and people assigned female at birth receive testosterone. Overall results found hormone replacements were associated with higher rates of cardiac events, mostly related to dangerous blood clots, but were not associated with higher rates of death.

Compared with hospitalised patients with gender dysphoria who had never used HRT, those taking gender affirmation HRT had higher rates for a range of in-hospital cardiovascular events:

  • ST-elevation myocardial infarction (OR 5.90, 95% CI 1.07-32.42)
  • Ischaemic cerebrovascular accident (OR 7.15, 95% CI 2.74-18.67)
  • Non-ST-elevation myocardial infarction (OR 3.30, 95% CI 1.20-9.04)
  • Pulmonary embolism (OR 4.92, 95% CI 2.08-11.62)

“It’s all about risks and benefits. Starting transitioning is a big part of a person’s life and helping them feel more themselves, but hormone replacement therapy also has a lot of side effects – it’s not a risk-free endeavour,” said Ibrahim Ahmed, MD, a third-year resident at Mercy Catholic Medical Center in Darby, Pennsylvania and the study’s lead author.

HRT was not associated with any increase in deaths, incident atrial fibrillation, diabetes, hypertension, haemorrhagic stroke, or heart failure.

Both oestrogen and testosterone are known to increase the clotting activity of blood, which could explain the increase in clotting-related cardiovascular events, researchers said. Those taking hormone replacement therapy also had higher rates of substance use disorder and hypothyroidism.

“Looking at a person’s medical and family history should definitely be part of the screening protocol before they even start hormone replacement therapy,” Ahmed said. “It is also important that people considering this therapy are made aware of all the risks.”

One limitation of the study is that it only accounted for whether individuals had ever used any type of hormone replacement therapy. To better inform clinical decisions, researchers said it would be helpful to assess whether the duration of treatment, the age at which it is initiated or the type of hormone therapy used affects the risks.

“I’m curious to see if the method of administration alters the outcomes,” Ahmed said. “Is one way of giving hormone replacement therapy better or associated with a lower risk of cardiovascular outcomes? If so, then that should be the focus for how we give these patients their hormone replacement therapy going forward.”

In addition to considering ways to mitigate potential cardiovascular risks before starting hormone replacement therapy for individual patients, researchers said it will be important to continue to study potential long-term cardiovascular and other health effects of gender affirmation therapies as the use of these therapies become more common.

Source: American College of Cardiology

Categories : Cardiovascular Disease GenderTags :

Reproductive Factors in Women Linked to Cardiovascular Disease

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Source: American Heart Association

An earlier first birth, a higher number of live births, and starting periods at a younger age are all linked to a higher risk of cardiovascular problems in women, according to new research published in the Journal of the American Heart Association. The study, led by Imperial College London researchers, provides evidence for a causal relationship between sex-specific factors and cardiovascular disease in women, and identifies potential ways to mediate this increased risk.

The study is the most comprehensive analysis to date of reproductive factors specific to women and their links to a range of cardiovascular diseases, including atrial fibrillation (irregular heart rate), coronary heart disease, heart failure, and stroke. The researchers hope it will help doctors to better understand and monitor women’s risk factors and intervene where appropriate.

Imperial College London researchers led a team that analysed genetic data linked to women’s age at first birth, their number of live births, age at menarche, and age at menopause. They looked at previous studies involving more than 100 000 women.

Observational research has previously identified that some reproductive factors are associated with cardiovascular disease for women in later life, but such studies are limited as they have been unable to support a causal relationship.

By using a statistical technique called Mendelian Randomization, the researchers were able to show a link between the genes that predict reproductive factors and the risk of multiple cardiovascular diseases. This type of analysis enables researchers to cut through the noise of factors such as diet, economic background and physical activity levels that can otherwise complicate the overall picture, and so it points to causal links.

The analysis showed that earlier first birth, a higher number of live births, and earlier menarche were associated with a higher risk of atrial fibrillation, coronary artery disease, heart failure, and stroke in women. However, it did not find an association between the age of menopause and cardiovascular disease.

The researchers also found that much of the increased risk for earlier menarche resulted from this factor being associated with women having a higher body mass index (BMI). This means that lowering a person’s BMI could help to reduce this risk. The increased risk for earlier first birth could be partly limited by acting on traditional cardiometabolic risk factors, such as BMI, high cholesterol and high blood pressure.

Dr Maddalena Ardissino, lead author of the study, from the National Heart and Lung Institute at Imperial College London, said: “Women are often mischaracterised as being at low risk for cardiovascular disease, leading to delays in diagnosis. Even when they are diagnosed, they tend to receive less targeted treatment than men.

“This study shows a clear link between reproductive factors and cardiovascular disease. This doesn’t mean that women should worry if they’ve had their period at a young age, or if they had an early first birth. Our research shows that the additional risk of cardiovascular disease can be minimised if traditional risk factors like BMI and blood pressure are well-controlled. These findings highlight the need for doctors to monitor these risk factors closely in women and intervene where needed.”

Dr Fu Siong Ng, senior author for the study, said: “Many of the previous studies on cardiovascular disease have focused on men, but our research shows that there are sex-specific factors that influence the risk for women.

“While we cannot say exactly how much these factors increase the risk of cardiovascular disease, our study shows that reproductive history is important and it points towards a causal impact. We need to understand more about these factors to make sure that women get the best possible care.”

Further research is needed to understand the extent of the relationship between reproductive factors and cardiovascular disease risk, such as whether there is a linear or non-linear relationship between a factor and increased risk.

Source: Imperial College London

Categories : Gender NeurologyTags :

Lower Oestrogen Levels may Explain Migraine Increase During Menstruation

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Woman feeling dizzy and kneeling
Photo by RODNAE Productions from Pexels

New research published in Neurology may explain why migraine attacks are more common during menstruation. The researchers found that, as oestrogen levels fluctuate, for female migraine sufferers, levels of the protein calcitonin gene-related peptide (CGRP) that plays a key role in starting the migraine process also fluctuate.

“This elevated level of CGRP following hormonal fluctuations could help to explain why migraine attacks are more likely during menstruation and why migraine attacks gradually decline after menopause,” said study author Bianca Raffaelli, MD, of Charité – Universitätsmedizin Berlin. “These results need to be confirmed with larger studies, but we’re hopeful that they will help us better understand the migraine process.”

The matched cohort study involved three groups of female participants with episodic migraine, all with least three days with migraine in the month before the study. The groups were those with a regular menstrual cycle, those taking oral contraceptives, and those who had gone through menopause. Each group had 30 people, for a total of 180, and were age-matched to women without migraine history.

Researchers collected blood and tear fluid to determine CGRP levels. In those with regular menstrual cycles, the samples were taken during menstruation when oestrogen levels are low and around the time of ovulation, when levels are the highest. In those taking oral contraceptives, samples were taken during the hormone-free time and the hormone-intake time. Samples were taken once from postmenopausal participants at a random time.

The study found that female participants with migraine and a regular menstrual cycle had higher CGRP concentrations during menstruation than those without migraine. Those with migraine had blood levels of 5.95 picograms per millilitre (pg/ml) compared to 4.61pg/ml for those without migraine. For tear fluid, those with migraine had 1.20ng/ml compared to 0.4ng/ml for those without migraine.

In contrast, those taking oral contraceptives or were postmenopausal had similar CGRP levels in the migraine and non-migraine groups.

“The study also suggests that measuring CGRP levels through tear fluid is feasible and warrants further investigation, as accurate measurement in the blood is challenging due to its very short half-life,” Raffaelli said. “This method is still exploratory, but it is non-invasive.”

Raffaelli noted that while hormone levels were taken around the time of ovulation, they may not have been taken exactly on the day of ovulation, so the fluctuations in oestrogen levels may not be fully reflected.

Source: American Academy of Neurology

Categories : Gender Neurodegenerative DiseasesTags :

Sex Differences Could Lead to New Neuroprotective Treatments

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A new study published in the Journal of Experimental Medicine provides a strategy for finding treatments optimally tailored for women and men to prevent cognitive decline in aging as well as progression of neurodegenerative diseases by leveraging sex differences in the brain.

Ageing is associated with cognitive decline and brain atrophy, and is a major neurodegenerative disease risk. Studying sex differences in brain aging and neurodegenerative diseases can reveal new candidate treatment targets tailored for women and men.

One new approach to identifying neuroprotective treatments lies in understanding the role of sex chromosome gene expression in the brain as sex hormones wane during the ageing process.

UCLA researchers Dr Rhonda Voskuhl, Professor, and Dr Yuichiro Itoh, Associate Researcher, in the Department of Neurology, have created a roadmap to identify novel neuroprotective treatments tailored for women and men that leverage known sex differences in brain aging and neurodegenerative diseases.

Previously, research pursuing treatments for neurodegenerative diseases ignored sex differences in the brain and pooled data together from males and females, taking a “one size fits all” approach. This could dilute out robust effects that exist in one sex but not the other at the clinical research level and fail to capitalize on known disease modifiers in the discovery of new treatment targets at the basic research level.

In their study Voskuhl and Itoh write that known sex differences in the brain as well as the effect of higher expression of certain X chromosome genes in females (XX) compared to males (XY) can be assessed for their role in neurodegeneration during aging, a stage of life characterised by loss of potentially neuroprotective hormones in females (namely oestrogen in menopause) and males (testosterone in andropause). The study offers a roadmap for disentangling the contribution of these sex-specific factors, which can yield treatments optimized and targeted for each sex.

In the future, this roadmap can be used by researchers to discover targets on the X chromosome gene for development of modulatory treatments that prevent neurodegeneration and promote neural repair during brain aging.

“Given the aging population and lack of treatments to prevent cognitive decline during health and to reduce the risk for developing neurodegenerative diseases, it is now imperative to apply new strategies to identify neuroprotective treatments,” said Voskuhl. “Leveraging what is known about sex differences in multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease can reveal candidate treatment targets tailored for women and men affected by these conditions. Sex chromosome effects remain understudied and represent a promising frontier for discovery, particularly in the context of declining levels of sex hormones during menopause and andropause.”

Source: University of California – Los Angeles Health Sciences

Categories : Cardiovascular Disease GenderTags :

Female and Male Hearts may Respond Differently to Noradrenaline

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Source: Wikimedia CC0

A new study published in Science Advances shows that female and male hearts respond differently to the stress hormone noradrenaline. The study in mice may have implications for human heart disorders like arrhythmias and heart failure and how different sexes respond to various drugs.

Using fluorescence imaging, the researchers were able to see in real time and in vivo how a mouse heart responds to hormones and neurotransmitters, including noradrenaline.

The results reveal that male and female mouse hearts respond uniformly at first after exposure to noradrenaline. However, some areas of the female heart return to normal more quickly than the male heart, producing differences in the heart’s electrical activity.

“The differences in electrical activity that we observed are called repolarisation in the female hearts. Repolarisation refers to how the heart resets between each heartbeat and is closely linked to some types of arrhythmias,” said Jessica L. Caldwell, first author of the study.

“We know that there are sex differences in the risk for certain types of arrhythmias. The study reveals a new factor that may contribute to different arrhythmia susceptibility between men and women,” Caldwell said.

Methods

The novel imaging system uses a genetically modified ‘CAMPER’ mouse to emit light during a very specific chemical reaction in the heart: cAMP binding.

The cAMP molecule (an abbreviation of cyclic adenosine 3′,5;-monophosphate) is an intermediate messenger that turns signals from hormones and neurotransmitters, including noradrenaline, into action from heart cells.

The light signals from the CAMPER mouse are transmitted by a biosensor that uses a fluorescence signal that can be picked up at high speed and high resolution by a new imaging system specially designed for hearts. This allows the researchers to record the heart’s reaction to noradrenaline in real time, along with changes in electrical activity.

This new imaging approach revealed the differences in the breakdown of cAMP in female and male mice and the associated differences in electrical activity.

Including female mice leads to discoveries

The researchers had not planned to study sex-based responses, according to Crystal M. Ripplinger, senior author of the study. But the researchers started seeing a pattern of different reactions, which led them to realise the differences were sex-based.

When Ripplinger started her lab at the UC Davis School of Medicine over a decade ago, she exclusively used male animals. That was the norm for most research at the time. But several years ago, she began including male and female animals in her studies.

“Sometimes the data between the two sexes is the same. But if the data start to show variation, the first thing we do is look at sex differences. Using both male and female mice has revealed clues into differences we would never have suspected. Researchers are realising you can’t extrapolate to both sexes from only studying one,” Ripplinger said.

She notes that with the current study, it’s not clear what the differences in cAMP and electrical activity may mean.

“The response in the female mice may be protective – or it may not. But simply documenting that there is a measurable difference in the response to a stress hormone is significant. We are hoping to learn more in future studies,” Ripplinger said.

Source: University of California – Davis Health

Categories : Ageing GenderTags :

Sex and Age Influence the Circadian Rhythm

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In a new study published in the journal Science, researchers exploring circadian molecular rhythms were able to uncover the organisation of gene expression rhythms in particular human tissues, and found that sex and age are involved, with females having a more regular pattern of rhythms.

In model organisms, analysing molecular rhythms is usually done using time-stamped measurements, but such data are not readily available in humans. To work around this, the researchers used existing measurements from a large cohort of post-mortem donors, combined with a novel computer algorithm that was designed to assign internal clock times to nearly one thousand donors.

“Interestingly, the data-science algorithm we developed turned out to resemble models from magnetic systems, which are well studied in statistical physics,” says study leader Felix Naef at Ecole Polytechnique Fédérale de Lausanne. Using this innovative approach, the researchers obtained the first comprehensive and accurate whole-organism view of 24-hour gene expression rhythms in 46 human tissues.

While the core clock machinery properties are conserved across the body and do not change significantly with sex and age, their analysis also revealed extensive programs of gene expression rhythms across major compartments of metabolism, stress response pathways and immune function, and these programs peaked twice a day.

In fact, the emerging whole-body organisation of circadian timing shows that rhythmic gene expression occurs as morning and evening waves, with the timing in the adrenal gland peaking first, while brain regions displayed much lower rhythmicity compared to metabolic tissues.

Dividing the donors by sex and age revealed a previously unknown richness of sex- and age- specific gene expression rhythms spread across biological functions. Strikingly, gene expression rhythms were sex-dimorphic (different in males and females) and more sustained in females, while rhythmic programs were generally reduced with age across the body.

Sex-dimorphic rhythms were particularly noticeable in the liver’s “xenobiotic detoxification,” the process by which liver breaks down harmful substances. Additionally, the study found that with age, the rhythm of gene expression decreases in the heart’s arteries, which may explain why older people are more susceptible to heart disease. This information could be useful in the field of “chronopharmacology,” which is the study of how a person’s internal clock affects the effectiveness and side effects of medication.

This study provides new insights into the complex interplay between our body clock, sex, and age. By understanding these rhythms, we might find new ways of diagnosing and treating pathologies such as sleep disorders and metabolic diseases.

Source: Ecole Polytechnique Fédérale de Lausanne