Tag: sex differences

Categories : DermatologyTags : Leave a comment

Testosterone Increases Severity of Staph Skin Infections

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Study led by UTSW researchers defines how skin hormones influence bacteria and results in potential treatment for Staph infections

This laboratory image shows Staphylococcus aureus bacteria streaked in the shape of a sex steroid, like testosterone. The left shape is of wild-type S. aureus, with the lighter halo around the shape indicating haemolysis, or the breakdown of red blood cells, releasing their haemoglobin into the surrounding fluid. The right shape is a quorum-sensing mutant strain of S. aureus, which cannot damage blood cells.

Men are more susceptible than women to skin infections caused by Staphylococcus aureus bacteria, but the biological basis for this disparity has remained unclear. A new study led by UT Southwestern Medical Center researchers is the first to reveal that testosterone as a key driver of infection. The sex steroid activates a bacterial communication pathway known as quorum sensing, increasing skin cell death and promoting the destruction of red blood cells and white blood cells called neutrophils. 

Published in Nature Microbiology, the study also reported that a mirror-image form of testosterone, known as an enantiomer (ent-T), blocks quorum sensing and prevents S. aureus from damaging tissue in mouse models.

Senior author Tamia Harris-Tryon, MD, PhD, Associate Professor of Dermatology and Immunology at UT Southwestern, and first author Maria S. John, PhD, a UTSW postdoctoral researcher, have a patent pending for an ent-T-based therapeutic along with collaborators at the University of Colorado.

“This research has important implications for treating Staph skin infections and conditions complicated by Staphylococcus, such as atopic dermatitis, pemphigus, abscesses, and wound infections, including the deadliest skin infections caused by methicillin-resistant Staphylococcus aureus [MRSA],” Dr Harris-Tryon said. “It also explains why men are more susceptible to Staph infections.” 

S. aureus is the leading cause of skin infections. When it enters the bloodstream, it can cause septicaemia, a life-threatening infection that may lead to organ failure.

During infection, the bacteria use quorum sensing to detect neighbouring cells of the same species. As bacterial density rises, they produce short signalling molecules called auto-inducing peptides (AIP), which activate virulence programs and trigger toxin release, resulting in host-cell damage. 

The research team found that male skin cells consistently secrete higher levels of testosterone than female skin cells. They also found the same is true for male mice, which were significantly more susceptible to S. aureus colonisation and skin damage than female mice when exposed to a strain of MRSA. However, mice engineered to secrete less testosterone displayed greater resistance to the bacteria, while applying testosterone to the skin of female mice increased MRSA’s severity. 

In laboratory experiments, testosterone activated quorum sensing even in the absence of AIPs. Other sex steroids, including progesterone and oestrogen, had no measurable effect on quorum sensing. 

While using ent-T as an experimental control, the researchers unexpectedly identified its therapeutic potential. In lab tests, ent-T inhibited quorum sensing and reduced the bacteria’s virulence. The molecule also inhibited quorum sensing on male and female mice when applied to their skin. 

Dr Harris-Tryon won an Innovation Award from the UTSW Office for Technology Development in 2024 to fund development of an ent-T-based transdermal therapeutic for Staph.

“Our exciting finding suggests we can inhibit S. aureus virulence rather than killing the bacteria directly, an approach that prevents infection, preserves beneficial skin microbes, and reduces the selective pressure that drives antibiotic resistance while offering a potential new strategy to treat infections, including MRSA,” Dr. John said.

This work builds on Dr Harris-Tryon’s studies in 2023 and 2025 with Jeffrey McDonald, PhD, Professor in the Center for Human Nutrition and of Molecular Genetics at UTSW, which demonstrated sex-specific differences in skin hormone production. The team also has previously uncovered how the immune system stimulates testosterone production in skin cells. Dr Harris-Tryon said the current research builds on UT Southwestern’s longstanding leadership in steroid and skin hormone biology, a field in which the institution has been a global leader for decades.

Source: UT Southwestern

Categories : Mental Health NeurologyTags : Leave a comment

How Oestrogen in the Brain Impacts Stress and Trauma Response

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New research reveals how oestrogen levels in the brain influence vulnerability to stress-related memory problems, helping explain sex differences in PTSD risk.

Photo by Sherise Van Dyk on Unsplash

For some people, a single traumatic event like a shooting, a natural disaster or a violent assault, can leave an imprint that lingers long after the immediate danger has passed. Memories of that event may return with unusual intensity, shaping mood, behaviour, and mental health in ways that are difficult to predict. Others exposed to similar trauma recover without developing lasting memory problems or trauma-related symptoms.

Why those outcomes diverge is a central question in stress and trauma research. Clinicians have long observed that severe acute stress can permanently alter memory for some people but not others, and that women face roughly twice the lifetime risk of posttraumatic stress disorder (PTSD). Recent research from the University of Pennsylvania in collaboration with the University of California-Irvine suggests that part of the answer may lie in the brain’s biological state at the precise moment trauma occurs.

Elizabeth Heller, PhD, an associate professor of Pharmacology in the Perelman School of Medicine at the University of Pennsylvania, and her team in the Heller Lab, have now shed light on how the brain’s biological state at the time of stress, particularly its oestrogen levels, can shape vulnerability long after the acute stress has lifted. Heller helped uncover that oestrogen levels in the brain may play a surprising role in this vulnerability, and for both sexes. The study, published in Neuron, also provides new insight into why women are more likely than men to develop post-traumatic stress disorder (PTSD) and to face higher dementia risk later in life.

Unpacking oestrogen’s role in memory vulnerability

Oestrogen is widely known to support learning and memory. This study found that high levels of oestrogen in the hippocampus, a brain region critical for memory, help the brain’s cells change and adjust more easily. However, in the context of severe acute stress, this flexibility can increase vulnerability to stress-related memory problems.

Heller and the Penn team mapped how high levels of oestrogen interact with chromatin structure (the storage packaging up DNA inside cells) in the hippocampus to make some brains more susceptible to PTSD‑like memory changes.

The findings help explain why traumatic events such as natural disasters, mass violence, and assaults can cause long-term memory problems, and why women are roughly twice as likely as men to develop PTSD.

“A lot of what determines vulnerability is the state your brain is already in,” Heller explained. “If a traumatic event hits during a period when oestrogen is already unusually high, the resulting plasticity can amplify the impact in lasting ways, promoting vulnerability to stress. Even with these findings in hand, the word oestrogen can mislead readers into assuming the biology applies only to women. That assumption shaped public understanding for decades, but it doesn’t hold up against what this research, and years of foundational neuroscience, actually shows.

As Heller notes, oestrogen is a critical brain hormone in both sexes. It is produced locally in regions like the hippocampus where it helps regulate learning, mood, and responses to stress. Recognising that universality is essential to understanding what this study truly reveals.

“The striking thing is that oestrogen levels are actually high in both males and in females in some parts of the hormonal cycle. Thus, the effects of high oestrogen levels happen in both males and females,” Heller said. “We tend to treat oestrogen as a women’s health hormone, but the brain makes its own oestrogen, and it plays powerful roles in stress, memory, mood, and emotion across sexes.”

By Eric Horvath

Source: Penn Medicine

Categories : NeurologyTags :

X-chromosomes: A New Lens on Autism’s Sex Bias

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Autism has a significant and enduring sex bias, with roughly four boys diagnosed for every girl. For many years, experts have believed this disparity arises primarily from diagnostic inequities because much of autism research – and the screening tools that grew out of it – has historically focused on boys, effectively setting a male standard for what autism “looks like.” As a result, girls and women are more likely to be overlooked, misdiagnosed, or diagnosed much later in life.

This disparity has also shaped the science around autism. When fewer females with the condition are identified, fewer are included in research studies, creating a feedback loop where scientific understanding of autism in females remains limited. Because of this underrepresentation of females, it has been difficult for scientists to disentangle how much of the sex bias in autism reflects social inequities versus underlying biological differences between the sexes. 

While the search for biological explanations has largely lagged behind, one leading theory, known as the “female protective effect,” proposes that females may be biologically buffered against developing autism in a way males aren’t. 

The idea can be traced back to studies showing that females diagnosed with autism tend to carry a higher number of genetic mutations or “hits” than males with the condition, meaning that they require a higher load of the same genetic mutations for autism to manifest. But, until now, there’s been little clarity on the exact biological mechanism behind this apparent resilience.

Now, a perspective from the lab of Whitehead Institute Member David Page, published March 30 in Nature Genetics, proposes a genetic explanation for the female protective effect and suggests that biological differences between males and females contribute to autism’s strong sex bias.

The work is one of many projects from the Page lab uncovering the biological underpinnings of sex bias in everything from heart health and autoimmune disease to certain cancers. 

“The fact that we see sex biases in disease all across the body gives credence to the notion that the sex bias in autism isn’t simply emerging from diagnostic inequities and gendered expectations of what the conditions looks like,” says Page, who is also a professor of biology at Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute (HHMI).

The researchers propose that this protective effect extends beyond autism, and could help explain why 17 other congenital and developmental disorders predominately affect males. By characterizing the biological factors that make one sex more or less likely to develop certain health conditions, scientists see an opportunity to improve how these conditions are diagnosed and how people receive care.

“The fact that we see sex biases in disease all across the body gives credence to the notion that the sex bias in autism isn’t simply emerging from diagnostic inequities and gendered expectations of what the conditions looks like,” says Page.

Page and Harvard-MIT MD-PhD student Maya Talukdar trace the female protective effect to the X chromosome. Talukdar is a graduate student in Page’s lab and the lead author of the perspective. 

Most females have two X chromosomes (XX) while most males have one X and one Y chromosome (XY). Sex chromosomes can dial up and down the expression of thousands of genes on the other 22 pairs of chromosomes in a cell, impacting cell function across the entire body. 

Historically, scientists believed that the second X chromosome in females is largely inactive. But, in recent years, research out of the Page lab has shown that the so-called “inactive X,” also called Xi, plays a crucial role in regulating gene expression on the active X chromosome, and the rest of the chromosomes.

In this perspective, the researchers point to a subset of genes that are expressed from both the active and inactive X chromosome — often known as genes that “escape” X chromosome inactivation. Many of these genes are dosage-sensitive regulators of key cellular processes. These processes influence thousands of other genes across the genome, including many linked to autism. 

Because females have an extra copy of these regulatory genes expressed from Xi, Page and Talukdar propose that they may be better able to buffer the effects of autism-associated mutations than males.

The female protective effect beyond autism

This mechanism, the researchers say, extends beyond autism to a range of congenital and developmental diseases with a male bias. 

“Many of the other congenital or developmental conditions we’re pointing to aren’t subject to diagnostic inequities in the way autism is,” says Talukdar. “This strengthens the idea that the female protective effect is emerging from genetic differences in males and females.”

One example is pyloric stenosis, which like autism, affects four boys for every girl. Infants with the condition experience severe vomiting due to thickening of the pyloric sphincter, the passage between the stomach and small intestine. As with autism, girls with pyloric stenosis appear to require more genetic “hits” in order to develop the condition.

The researchers’ new framework of looking at Xi to understand sex differences in disease could impact treatment and care not just for conditions that predominately affect males, but also for those that are more common in women, such as autoimmune diseases. 

“Our biology isn’t one-size-fits-all,” Talukdar says “Sex differences clearly play a huge role in health, and it’s so important that we understand them.”

By Shafaq Zia

Source: Whitehead Institute for Biomedical Research

Categories : Pain ManagementTags :

Why is Migraine More Common in Women than Men?

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Photo by Andrea Piacquadio

Lakshini Gunasekera, Monash University; Caroline Gurvich, Monash University; Eveline Mu, Monash University, and Jayashri Kulkarni, Monash University

We’ve known for a long time that women are more likely than men to have migraine attacks.

As children, girls and boys experience migraine equally. But after puberty, women are two to three times more likely to experience this potentially debilitating condition.

Recently, an Australian study showed it may be even more common than we previously thought – as many as one in three women live with migraine.

For comparison, migraine affects roughly one in 15 men in Australia.

So, what’s behind the difference? Here’s what we know.

More than a headache

Migraine is not just a bad headache – it is a complex disorder that causes the brain to process sensory information abnormally.

This means “migraine brains” can have difficulty processing information from any of the five senses:

  • sight (leading to problems with light sensitivity and glare)
  • sound (leading to noise sensitivity)
  • smell (certain smells can trigger headaches)
  • touch (leading to face or scalp tenderness)
  • taste (causing distorted taste, nausea and vomiting).

Migraine attacks typically last anywhere from four hours to three days – but can be longer.

In addition to the symptoms above, attacks can include throbbing head pain, dizziness, fatigue and difficulty concentrating. It is these extra symptoms that help diagnose migraine – not the location of head pain or pain severity.

Why are attacks more frequent in women?

Puberty is when the difference between men and women emerges. This is when our bodies massively increase the production of sex hormones.

People are often surprised to learn that both men and women produce oestrogen, progesterone and testosterone. Testosterone levels are higher in men, whereas women have higher levels of oestrogen and progesterone.

However, it is not just the type of hormone that makes a difference, but the way they fluctuate over time.

For many women, there are certain “milestone moments” when their migraine tends to worsen due to hormonal fluctuations – puberty, menstruation, pregnancy and perimenopause (the lead-up to your final period).

For example, some women notice migraine flare-ups every month, linked to phases in their monthly menstrual cycle when oestrogen levels drop.

They might even be able to predict when their period will start, as migraine attacks typically start a few days before the bleeding.

How hormones affect the brain

Women with migraine can be more sensitive to hormonal changes. This is particularly the case for sudden decreases in oestrogen. But even more subtle changes to hormone levels can cause migraine attacks.

These hormonal changes can activate brain processes that trigger migraine, such as cortical spreading depression. This is a very slow wave of electrical activity that spreads in the brain, causing some areas to function more slowly than others after it passes.

Decrease in oestrogen can also affect how we receive and process information through the trigeminal nerve. This plays a key role in the onset and maintenance of migraine pain.

Diagram showing the trigeminal nerve in the head.
Oestrogen can affect how we process information through the trigeminal nerve. ttsz/Getty

All kinds of fluctuations can be a trigger

Pregnancy can often destabilise migraine again and make attacks more likely, even when someone has previously enjoyed a period of good migraine control.

Migraine symptoms often become uncontrolled in the first trimester in particular, due to rapid hormonal changes needed to sustain a pregnancy. This usually settles in the second and third trimesters, when hormonal changes stabilise.

However, giving birth is yet another change.

Towards the end of pregnancy, oestrogen levels can be 30 times higher than pre-pregnancy levels, and progesterone can be 20 times higher. When these hormones plummet back to normal after giving birth, migraine attacks can often sharply worsen again.

Perimenopause can also involve random surges of oestrogen from the dwindling supplies of eggs within the ovaries – which previously produced these hormones cyclically and in abundance. This irregular hormone production can cause random spikes in migraine attacks. It can be extra challenging when combined with other symptoms of menopause such as hot flushes or mood changes.

Hormonal contraceptives and menopause hormone therapy can also affect migraine control. Sometimes, supplementing hormones at a regular, steady daily dose can help manage the hormone-sensitive headaches and other symptoms. However, for others, adding extra hormones can cause head pain to flare up.

Does migraine run in the family?

Genes also play a role. It’s not a coincidence that migraine is passed down in families through the maternal side.

This is because mothers pass on mitochondria to children (while fathers do not). Mitochondria are parts inside the cell that control energy.

People with migraine have fewer functional enzymes within their mitochondria, meaning their brains are in an energy-deficient state. This worsens with migraine attacks as there is even more stress to the system.

This is also why extra stress (such as sleep deprivation, missed meals, or emotional stress) can trigger a migraine and worsen pain.

There is also a strong link between migraine in women and anxiety and depression – conditions women are more likely to develop in response to stressful life events.

Knowing your own patterns

If you suspect hormones may be affecting your migraine attacks, it is helpful to keep a diary of symptoms, including headaches. Mark each day per month where you get migraine symptoms, as well as your period, to find patterns.

Identifying patterns in pain flares helps doctors guide you to a personalised medication plan, which may include hormone therapies or non-hormonal therapies.

Lakshini Gunasekera, PhD Candidate in Neurology, Monash University; Caroline Gurvich, Associate Professor and Clinical Neuropsychologist, Monash University; Eveline Mu, Research Fellow in Women’s Mental Health, Monash University, and Jayashri Kulkarni, Professor of Psychiatry, Monash University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Categories : Cardiovascular DiseaseTags :

Gap in Onset of Cardiovascular Disease Still Persists Between Sexes

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Credit: American Heart Association

Historical data indicate that men develop coronary heart disease (CHD) 10 years before women. A recent study in the Journal of the American Heart Association indicates that this sex gap still remains.

Investigators analysed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, in which US adults aged 18–30 years enrolled in 1985–1986 and were followed through August 2020.

Among 5112 participants (54.5% female, 51.6% Black) with an average age of 24.8 years at enrolment and a median follow-up of 34.1 years, men had a significantly higher cumulative incidence of cardiovascular disease. They had higher cumulative incidence rates of the cardiovascular disease subtypes of CHD and heart failure compared with women, but no difference in stroke.

Men reached a 5% incidence of cardiovascular disease 7.0 years earlier than women (50.5 versus 57.5 years). CHD was the most frequent cardiovascular disease subtype, and men reached a 2% incidence 10.1 years earlier than women. There were no significant differences in the age at which men and women reached a 2% incidence for stroke (57.5 versus 56.9 years) or a 1% incidence for heart failure (48.7 versus 51.7 years)

Differences emerged in the fourth decade of life and were not explained after accounting for differences in cardiovascular health.

“Sex differences in cardiovascular disease risk are apparent by age 35, highlighting the importance of initiating risk assessment and prevention strategies in young adulthood,” said corresponding author Alexa Freedman, PhD, of the Northwestern University Feinberg School of Medicine.

Source: Wiley

Categories : Mental Health PaediatricsTags :

Rates of Autism in Girls and Boys May Be More Equal than Previously Thought

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Study raises questions around why female individuals are diagnosed later than males

Photo by Ben Wicks on Unsplash

Autism has long been viewed as a condition that predominantly affects male individuals, but a study from Sweden published by The BMJ shows that autism may actually occur at comparable rates among male and female individuals.

The results show a clear female catch-up effect during adolescence, which the researchers say highlights the need to investigate why female individuals receive diagnoses later than male individuals.

The prevalence of autism spectrum disorder (ASD) has increased over the past three decades, with a high male-to-female diagnosis ratio of around 4:1.

The increase in prevalence is thought to be linked to factors including wider diagnostic criteria and societal changes (eg, parental age), whilst the high male to female ratio has been attributed to better social and communication skills among girls, making autism more difficult to spot. However so far no large study has examined these trends over the life course.

To address this, researchers used national registers to analyse diagnosis rates of autism for 2.7 million individuals born in Sweden between 1985 and 2022 who were tracked from birth to a maximum of 37 years of age.

During this follow-up period of more than 35 years, autism was diagnosed in 78,522 (2.8%) of individuals at an average age of 14.3 years.

Diagnosis rates increased with each five year age interval throughout childhood, peaking at 645.5 per 100,000 person years for male individuals at age 10-14 years and 602.6 for female individuals at age 15-19 years.

However, while male individuals were more likely to have a diagnosis of autism in childhood, female individuals caught up during adolescence, giving a male to female ratio approaching 1:1 by age 20 years.

This is an observational study and the authors acknowledge that they did not consider other conditions associated with autism, such as ADHD and intellectual disability. Nor were they able to control for shared genetic and environmental conditions like parental mental health.

However, they say the study size and duration enabled them to link data for a whole population and disentangle the effects of three different time scales: age, calendar period and birth cohort.

As such, they write: “These findings indicate that the male to female ratio for autism has decreased over time and with increasing age at diagnosis. This male to female ratio may therefore be substantially lower than previously thought, to the extent that, in Sweden, it may no longer be distinguishable by adulthood.”

“These observations highlight the need to investigate why female individuals receive diagnoses later than male individuals,” they conclude.

These findings align with recent research and seem to support the argument that current practices may be failing to recognise autism in many women until later in life, if at all, says Anne Cary, patient and patient advocate, in a linked editorial.

She notes that studies like this are essential to changing the assumption that autism is more prevalent in male individuals than in female individuals, but points out that as autistic female individuals await proper diagnosis, “they are likely to be (mis)diagnosed with psychiatric conditions, especially mood and personality disorders, and they are forced to self-advocate to be seen and treated appropriately: as autistic patients, just as autistic as their male counterparts.”

Source: BMJ Group

Categories : Cardiovascular DiseaseTags :

Men’s Heart Attack Risk Climbs by Mid-30s, Years Before Women

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Decades-long US study suggests prevention and screening should start earlier in adulthood

Pexels Photo by Freestocksorg

Men begin developing coronary heart disease – which can lead to heart attacks – years earlier than women, with differences emerging as early as the mid-30s, according to a large, long-term study led by Northwestern Medicine.

The findings, based on more than three decades of patient follow-up, suggest that heart disease prevention and screening should start earlier in adulthood, particularly for men.

“That timing may seem early, but heart disease develops over decades, with early markers detectable in young adulthood,” said study senior author Alexa Freedman, assistant professor of preventive medicine at Northwestern University Feinberg School of Medicine.

“Screening at an earlier age can help identify risk factors sooner, enabling preventive strategies that reduce long-term risk.”

Older studies have consistently shown that men tend to experience heart disease earlier than women. But over the past several decades, risk factors like smoking, high blood pressure and diabetes have become more similar between the sexes. So, it was surprising to find that the gap hasn’t narrowed, Freedman said.

To better understand why sex differences in heart disease persist, Freedman and her colleagues say it’s important to look beyond standard measures such as cholesterol and blood pressure and consider a broader range of biological and social factors.

Tracking heart disease from young adulthood

The study analysed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, which enrolled more than 5100 Black and white adults ages 18 to 30 in the mid-1980s and followed them through 2020.

Because participants were healthy young adults at enrollment, the scientists were able to pinpoint when cardiovascular disease risk first began to diverge between men and women. Men reached 5% incidence of cardiovascular disease (defined broadly to include heart attack, stroke and heart failure) about seven years earlier than women (50.5 versus 57.5 years).

The difference was driven largely by coronary heart disease. Men reached a 2% incidence of coronary heart disease more than a decade earlier than women, while rates of stroke were similar and differences in heart failure emerged later in life. “This was still a relatively young sample – everyone was under 65 at last follow-up – and stroke and heart failure tend to develop later in life,” Freedman explained.

Beyond traditional risk factors

The scientists examined whether differences in blood pressure, cholesterol, blood sugar, smoking, diet, physical activity and body weight could explain the earlier onset of heart disease in men. While some factors, particularly hypertension, explained part of the gap, overall cardiovascular health did not fully account for the difference, suggesting other biological or social factors may be involved.

A critical age: 35

One of the most striking findings was when the risk gap opened. The scientists found that men and women had similar cardiovascular risk through their early 30s. Around age 35, however, men’s risk began to rise faster and stayed higher through midlife. Heart disease screening and prevention efforts often focus on adults over 40. The new findings suggest that approach may miss an important window.

The authors highlight the relatively new American Heart Association’s PREVENT risk equations, which can predict heart disease starting at age 30, as a promising tool for earlier intervention.

By Ben Schamisso

Source: Northwestern University

Categories : Gastrointestinal Obstetrics & GynaecologyTags :

Do Hormones Explain Why Women Experience More Gut Pain?

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UCSF researchers discover that oestrogen can turn on pain signals associated with conditions like irritable bowel syndrome.

A zoomed in image of the lining of the colon. Cells that produce the hormone  PYY (peptide YY) are in green. Cells that produce the neurotransmitter serotonin are in magenta. PYY triggers the release of serotonin, which activates pain-sensing nerve fibers. Image by Archana Venkataraman/UCSF

Women are dramatically more likely than men to suffer from irritable bowel syndrome (IBS), a chronic condition causing abdominal pain, bloating, and digestive discomfort. Now, scientists at UC San Francisco have discovered why.

Oestrogen, the researchers report in Science, activates previously unknown pathways in the colon that can trigger pain and make the female gut more sensitive to certain foods and their breakdown products. When male mice were given oestrogen to mimic the levels found in females, their gut pain sensitivity increased to match that of females.

The findings not only explain the female predominance in gut pain disorders but also point to potential new ways to treat the conditions.

“Instead of just saying young women suffer from IBS, we wanted rigorous science explaining why,” said Holly Ingraham, PhD, professor UCSF and co-senior author of the study. “We’ve answered that question, and in the process identified new potential drug targets.”

The research also suggests why low-FODMAP diets – which eliminate certain fermentable foods, such as onions, garlic, honey, wheat, and beans – help some IBS patients, and why women’s gut symptoms often fluctuate with their menstrual cycles.

“We knew the gut has a sophisticated pain-sensing system, but this study reveals how hormones can dial that sensitivity up by tapping into this system through an interesting and potent cellular connection,” said co-senior author David Julius, PhD. Julius won the 2021 Nobel Prize for Physiology or Medicine for his work on pain sensation.

Search for oestrogen

Previous research had hinted that oestrogen was to blame for higher rates of IBS in females, but not why. To understand how oestrogen might be involved, Ingraham’s and Julius’s teams first needed to see exactly where the hormone was working in the gut.

“At the time I started this project, we didn’t know where and how oestrogen signalling is set up in the female intestine,” said Archana Venkataraman, PhD, a postdoc in Ingraham’s lab and co-first author of the research. “So, our initial step was to visualise the oestrogen receptor along the length of the female gut.”

The team expected to see oestrogen receptors in enterochromaffin (EC) cells, which were already known to send pain signals from the gut to the spinal cord. Instead, they got a surprise: oestrogen receptors were clustered in the lower part of the colon and in a different cell type known as L-cells.

The scientists pieced together a complex chain reaction that occurs when oestrogen binds to the L-cells. First, oestrogen causes L-cells to release a hormone called PYY (peptide YY). PYY then acts on neighbouring EC cells, triggering them to release the neurotransmitter serotonin, which activates pain-sensing nerve fibres. In female mice, removing the ovaries or blocking oestrogen, serotonin, or PYY dramatically reduced the high gut pain observed in females.

For decades, scientists believed PYY primarily suppressed appetite – drug companies even tried developing it as a weight-loss medication. But those clinical trials failed due to a troubling side effect that was never fully explained; participants experienced severe gut distress. The new findings mesh with this observation and suggest a completely new role for PYY.

“PYY had never been directly described as a pain signal in the past,” said co-first author Eric Figueroa, PhD, a postdoc in Julius’ lab. “Establishing this new role for PYY in gut pain reframes our thinking about this hormone and its local effects in the colon.”

This video shows what happens to the enterochromaffin (EC) cells in the colon when they are treated with PYY. Upon PYY treatment, calcium activity increases in the EC cell, causing it to fluoresce more brightly as it releases serotonin that is detected by nearby pain-sensing nerve fibres. Video by Eric Figueroa/UCSF

A link between IBS and diet

Increased PYY wasn’t the only way that L-cells responded to oestrogen. Levels of another molecule, called Olfr78, also went up in response to the hormone. Olfr78 detects short-chain fatty acids – metabolites produced when gut bacteria digest certain foods. With more Olfr78 receptors, L-cells become hypersensitive to these fatty acids and are more easily triggered to become active, releasing more PYY.

“It means that oestrogen is really leading to this double hit,” said Venkataraman. “First it’s increasing the baseline sensitivity of the gut by increasing PYY, and then it’s also making L-cells more sensitive to these metabolites that are floating around in the colon.”

The observation may explain why low-FODMAP diets help some IBS patients. FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) are carbohydrates that gut bacteria ferment into those same fatty acids sensed by Olfr78. By eating fewer FODMAPs, patients may be preventing the activation of Olfr78, and, in turn, keeping L-cells from churning out more of the pain signalling PYY.

While men have this same cellular pathway, their lower oestrogen levels keep it relatively quiet. However, the pathway could engage in men taking androgen-blocking medications, which block the effects of testosterone and can elevate oestrogen in some cases, potentially leading to digestive side-effects.

The new work suggests potential ways to treat IBS in women and men alike.

“Even for patients who see success with a low-FODMAP diet, it’s nearly impossible to stick to long term,” Ingraham said. “But the pathways we’ve identified here might be leveraged as new drug targets.”

The researchers are now studying how such drugs might work, as well as asking questions about what other hormones, such as progesterone, might play a role in gut sensitivity and how pregnancy, lactation, and normal menstrual cycles affect intestinal function.

By Sarah C.P. Williams

Source: University of California – San Francisco

Categories : CancerTags :

Why are Men More Likely to Develop Multiple Myeloma than Women?

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Study identifies several clinical features involved.

Photo by Daniil Onischenko on Unsplash

Rates of multiple myeloma (MM), the second most common blood cancer in the United States, are increasing and are twice as high in men than in women. A new study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society, provides insights that may help to explain this disparity.

To investigate the sex difference in MM, researchers analyzed data on 850 patients with newly diagnosed MM enrolled in the Integrative Molecular And Genetic Epidemiology (IMAGE) study at the University of Alabama at Birmingham.

Compared with female patients, male patients were more likely to have advanced (International Staging System stage III) disease at the time of diagnosis. Males were also more likely to have high myeloma load—serum monoclonal protein (an abnormal protein produced by cancerous blood cells), more organ failure (especially kidney failure), and bone damage. Men were less likely than women to have low bone mineral density, and myeloma-defining features tended to differ between the two sexes. These differences were apparent even after taking numerous factors into account – including race, age, body mass index, education, income, smoking, and alcohol use.

Analyses suggested that certain chromosomal abnormalities that lead to initiation of myeloma occurring more often in younger males may help to explain some of the differences seen in this study.

“This research suggests that sex-specific mechanisms promote multiple myeloma pathogenesis, which may account for the excess risk seen in men,” said lead author Krystle L. Ong, PhD, of the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham. “These findings may be used to improve risk stratification, diagnosis, and tailored treatments for both men and women with newly diagnosed multiple myeloma or related early precursor conditions.”

Source: Wiley

Categories : GenderTags :

Men at Greater Risk of Major Health Effects of Diabetes than Women

On By ModernMedia

Cases of cardiovascular, leg/foot, kidney complications, and eye disease all higher in men
Sex differences in complication rates persist regardless of disease duration

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Men are at greater risk than women of the major health effects of diabetes (types 1 and 2), suggests a long term study published online in the Journal of Epidemiology & Community Health.

Rates of cardiovascular disease, leg, foot, and kidney complications, and the sight-threatening eye disease diabetic retinopathy are all higher in men, regardless of whether they had diabetes for more or less than 10 years, the findings show.

The global prevalence of diabetes is similar in men and women, and is projected to rise to 783 million by 2045, note the researchers.

But while cardiovascular disease is more common in men, overall, it’s not clear if this sex difference is apparent in the incidence of the complications associated with diabetes, say the researchers. Nor is it clear whether the length of time lived with diabetes might be influential, they add.

To explore this further, the researchers drew on survey responses from the 45 and Up Study, Australia, a large prospective study of 267 357 people over the age of 45 living in New South Wales (NSW).

These responses were linked to medical records for a total of 25 713 people, all of whom had either type 1 or type 2 diabetes, to monitor the development of any of the major health issues associated with diabetes

These include cardiovascular disease – ischaemic heart disease, mini stroke or TIA, stroke, heart failure, diabetic cardiomyopathy; eye problems – cataract, diabetic retinopathy; leg/foot problems – peripheral neuropathy (nerve damage), ulcers, cellulitis, osteomyelitis (bone inflammation), peripheral vascular disease (poor circulation), and minor or major amputation; and kidney problems – acute kidney failure, chronic kidney disease, chronic kidney failure, dialysis, and kidney transplant.

Almost half of the group were aged 60 to 74, and over half (57%; 14,697) were men, a higher proportion of whom were overweight (39% vs 29% of women) and had a history of heart disease.

Although a similar proportion of men and women were current smokers, a higher proportion of men were ex-smokers: 51% vs  29% of the women.

Of the 19 277 (75%) people with diabetes whose age was recorded at their diagnosis, 58% had been living with the disease for less than a decade and 42% had lived with it for 10 or more years.

Men had higher rates, and were at greater risk, of the complications associated with diabetes.

Over an average monitoring period of 10 years, and after factoring in age, 44% of the men experienced a cardiovascular disease complication while 57% had eye complications. Similarly, 25% of the men had leg/foot complications, and 35% kidney complications. The equivalent figures for women were, respectively, 31%, 61%, 18% and 25%.

Overall, men were 51% more likely to develop cardiovascular disease than women, 47% more likely to have leg and foot complications, and 55% more likely to have kidney complications.

Although there was little difference in the overall risk of eye complications between the sexes, men were at slightly higher risk (14%) of diabetic retinopathy.

While complication rates rose in tandem with the number of years lived with diabetes for both men and women, the sex difference in complication rates persisted.

By way of an explanation, the researchers point out that the men in the study were more likely to have well known risk factors. Men may also be less likely to make lifestyle changes, take preventive meds, or get health checks to lower their risks, they suggest.

This is an observational study, and as such, no firm conclusions can be drawn about causal factors, added to which people with a history of complications were excluded from the study. And information on potentially influential factors, such as diabetes medications, and glucose, blood fat, and blood pressure control wasn’t available.

But based on their findings, the researchers suggest: “For every 1000 people with diabetes, our findings suggest that an average of 37, 52, 21, and 32 people will develop cardiovascular disease, eye, lower limb, and kidney complications every year.”

While the risks of complications are lower in women with diabetes, they are still high, emphasise the researchers.

And they conclude: “Although men with diabetes are at greater risk of developing complications, in particular [cardiovascular disease], kidney and lower-limb complications, the rates of complications are high in both sexes.

“The similar sex difference for those with shorter compared with longer diabetes duration highlights the need for targeted complication screening and prevention strategies from the time of diabetes diagnosis.

“Further investigation into the underlying mechanisms for the observed sex differences in diabetes complications are needed to inform targeted interventions.”

Source: BMJ Group