Tag: oestrogen

Categories : NeurologyTags :

How Oestrogen can Trigger Nerve Impulses in Milliseconds

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Photo by Julian Jagtenberg on Pexels

Oestrogen, the major female ovarian hormone, can trigger nerve impulses within milliseconds to regulate a variety of physiological processes. At Baylor College of Medicine, Louisiana State University and collaborating institutions, researchers discovered that oestrogen’s fast actions are mediated by the coupling of the oestrogen receptor-alpha (ER-alpha) with an ion channel protein called Clic1.

Clic1 controls the fast flux of electrically charged chloride ions through the cell membrane, which neurons use for receiving, conducting and transmitting signals. The researchers propose that interacting with the ER-alpha-Clic1 complex enables oestrogen to trigger fast neuronal responses through Clic1 ion currents. The study appeared in Science Advances.

“Oestrogen can act in the brain to regulate a variety of physiological processes, including female fertility, sexual behaviours, mood, reward, stress response, cognition, cardiovascular activities and body weight balance. Many of these functions are mediated by oestrogen binding to one of its receptors, ER-alpha,” said co-corresponding author Dr Yong Xu, professor of pediatrics – nutrition and associate director for basic sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor. 

Fast and slow

It is well known that, upon stimulation by oestrogen, ER-alpha enters the cell nucleus where it mediates the transcription of genes. This classical mode of action as a nuclear receptor takes minutes to hours.

“Oestrogen also can change the firing activity of neurons in a manner of milliseconds, but it was not clear how this happens,” Xu said. “In this case, it did not make sense to us that the minutes-long nuclear receptor function of ER-alpha was involved in such a rapid action. We explored the possibility that ion channels, proteins in the cell membrane that regulate the fast flux of ions, mediated oestrogen’s quick actions.”

In the current study, working with cell lines and animal models, the team searched for cell membrane proteins that interact with ER-alpha. They found that protein Clic1, for chloride intracellular channel protein-1, can physically interact with ER-alpha. Clic1has been implicated in the regulation of neuronal excitability, so the researchers considered it a candidate to mediate oestrogen-triggered fast actions.

“We discovered that oestrogen enhances Clic1-mediated ion currents, and eliminating oestrogen reduced such currents,” Xu said. “In addition, Clic1 currents are required for oestrogen to induce rapid responses in neurons. Also, disrupting the Clic1 gene in animal models blunted oestrogen regulation of female body weight balance.”

The findings suggest that other nuclear receptors could also interact with ion channels, a possibility the researchers look forward to studying in the future.

“This study was conducted with female mice. However, Clic1 is also present in males. We are interested in investigating its role in male physiology,” Xu said.

Chloride channels are not as well studied as other ion channels, such as potassium, sodium or calcium channels. “We are among the first to study the role Clic1 plays in female physiology,” Xu said. “We hope that our findings will inspire other groups in the field to expand these promising investigations.”

Source: Baylor College of Medicine

Categories : CancerTags :

New Trial Flips the Script for Hormonal Treatment of Breast Cancer

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Photo by National Cancer Institute

For decades, hormonal treatment of breast cancer has been going in one direction: blocking oestrogen. Now, a global study has discovered there may be another, less toxic way to defeat the most common form of breast cancer. The results, published in The Lancet Oncology, showed that the androgen receptor (AR) agonist enobosarm, is effective against oestrogen receptor-positive (ER+) breast cancer, which constitutes up to 80% of all breast cancer cases.

“The effectiveness of enobosarm lies in its ability to activate the AR and trigger a natural defence mechanism in breast tissue, thereby slowing the growth of ER+ breast cancer, which relies on the hormone oestrogen to grow and spread,” said senior co-author Professor Wayne Tilley, Director of the Dame Roma Mitchell Cancer Research Laboratories at the University of Adelaide.

“This clinical study is supported by our pre-clinical research, previously published in Nature Medicine, which established that the AR is a tumour suppressor in both normal breast tissue and ER+ breast cancer.”

Along with investigators from the University of Adelaide and Dana-Farber Cancer Institute (DFCI) in Boston, USA, the international study also included researchers from the University of Liverpool in the UK and other experts around the world.

The team assessed enobosarm’s efficacy and safety in 136 postmenopausal women with advanced or metastatic ER-positive, HER2-negative breast cancer.

Enobosarm showed significant anti-tumour activity and was well-tolerated by patients, without adversely affecting their quality of life or causing masculinising symptoms.

This discovery represents the first advancement in hormonal treatment of ER+ breast cancer in decades and offers a promising new oral treatment strategy for the most prevalent form of breast cancer.

The new hormonal strategy differs from the existing standard-of-care hormonal treatments, which have been around for decades and involve suppressing oestrogen activity in the body or inhibiting the ER.

Although successful initially, treatments targeting ER can cause severe side effects and treatment-resistant progression of the disease is common.

“Our findings are very promising. They demonstrate that stimulating the androgen receptor pathway with enobosarm can be beneficial,” said senior co-author and study Principal Investigator Dr Beth Overmoyer from DFCI.

“This is the first time a non-oestrogen receptor hormonal treatment approach has been shown to be clinically advantageous in ER+ breast cancer. The study supports further investigation of enobosarm in earlier stages of breast cancer as well as in combination with targeted therapies, such as ribociclib, a CDK 4/6 inhibitor.”

estrogen to grow and spread,” said senior co-author Professor Wayne Tilley, Director of the Dame Roma Mitchell Cancer Research Laboratories at the University of Adelaide.

“The data strongly encourages more clinical trials for AR-stimulating drugs in treating AR-positive and ER-positive breast cancer. The fact that this drug is well-tolerated also opens possibilities for its use in breast cancer prevention,” said co-author Dr Stephen Birrell, a clinical affiliate of the University of Adelaide.

Source: University of Adelaide

Categories : Diseases, Syndromes and Conditions Obstetrics & GynaecologyTags :

Prescribed Oestrogen and Factor V Leiden Mutation More than Double Blood Clot Risk

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Source: Wikimedia CC0

New research from Queen Mary University of London, published in iScience, shows an increased risk of blood clots in women who have any combination of Factor V Leiden gene mutation, oestrogen use, or common medical conditions – specifically: obesity, high blood pressure, high cholesterol, and kidney disease.

Women with the Factor V Leiden (FVL) gene mutation who had been prescribed oestrogen had more than double the risk of blood clotting compared to women who did not have this mutation. And almost 20% of the women who carry FVL, were prescribed oestrogen and had two medical conditions suffered a blood clot. The presence of the FVL gene made a substantial difference to risk, with only around 5% of women taking oestrogen and having two conditions suffering a clotting event.

The study also found that a woman with obesity, hypertension, high cholesterol, and kidney disease (not uncommon in a clinical setting) had an 8 times greater chance of blood clotting compared to a woman with none of these conditions. This amounted to roughly one in every six women with the four conditions in the study suffering a blood clot. Three medical conditions meant a five times greater chance of blood clotting, and two medical conditions meant a two times greater chance.

One in three women who had the FVL gene mutation and three of the medical conditions examined also suffered a blood clotting event.

The researchers examined the health data of 20 048 British-Bangladeshi and British-Pakistani women from the Genes & Health project, a large community-based genetics study. While oestrogen use, FVL, and common medical conditions are all known risk factors of blood clots, studies have not looked at the combined risk of these factors together on blood clot prevalence.

Women are commonly prescribed oestrogen, both through oral contraception containing the hormone and as part of post-menopausal hormone replacement therapy.

Professor Sir Mark Caulfield, from Queen Mary University of London, said: “Our study gives a more complete picture of blood clotting in Bangladeshi and Pakistani communities who have previously been underrepresented in research.

“Genetic testing of the FVL gene mutation could give a clearer sense of someone’s personalised risk of this potentially fatal complication if they were prescribed oestrogen.”

Source: Queen Mary University London

Categories : Mental Health Obstetrics & GynaecologyTags :

New Study Finds Depression Risk with Hormonal Contraceptive Use

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The possibility that contraceptive pills might have negative effects on mental health and even lead to depression has long been debated. Now, evidence published in Epidemiology and Psychiatric Sciences shows that contraceptive pills are in fact linked to depression, with teenage girls at particularly increased risk.

This study is one of the largest and widest-ranging to date, following more than a quarter of a million women from UK Biobank from birth to menopause.

The researchers collected data about women’s use of contraceptive pills, the time at which they were first diagnosed with depression and when they first experienced symptoms of depression without receiving a diagnosis. The method of contraception studied was combined contraceptive pills, which contain progestogen and oestrogen. Progestogen prevents ovulation and thickens the cervical mucus to prevent sperms from entering the uterus, while oestrogen thins the uterine lining to hinder the implantation of a fertilised egg.

“Although contraception has many advantages for women, both medical practitioners and patients should be informed about the side-effects identified in this and previous research,” says Therese Johansson at Uppsala University, one of the researchers leading the study.

According to the study, women who began to use contraceptive pills as teenagers had a 130% higher incidence of symptoms of depression, while the corresponding increase among adult users was 92%.

“The powerful influence of contraceptive pills on teenagers can be ascribed to the hormonal changes caused by puberty. As women in that age group have already experienced substantial hormonal changes, they can be more receptive not only to hormonal changes but also to other life experiences,” Johansson says.

The researchers were also able to see that the increased incidence of depression declined when the women continued to use contraceptive pills after the first two years. However, teenage users of contraceptive pills still had an increased incidence of depression even after stopping using the pill, which was not observed in adult users of contraceptive pills.

“It is important to emphasise that most women tolerate external hormones well, without experiencing negative effects on their mood, so combined contraceptive pills are an excellent option for many women. Contraceptive pills enable women to avoid unplanned pregnancies and they can also prevent illnesses that affect women, including ovarian cancer and uterine cancer. However, certain women may have an increased risk of depression after starting to use contraceptive pills.”

The findings of the study point to a need for healthcare professionals to be more aware of possible links between different systems in the body, such as depression and the use of contraceptive pills. The researchers conclude that it is important for care providers to inform women who are considering using contraceptive pills of the potential risk of depression as a side-effect of the medicine.

“Since we only investigated combined contraceptive pills in this study, we cannot draw conclusions about other contraceptive options, such as mini pills, contraceptive patches, hormonal spirals, vaginal rings or contraceptive rods. In a future study, we plan to examine different formulations and methods of administration. Our ambition in comparing different contraceptive methods is to give women even more information to help them take well-informed decisions about their contraceptive options,” Johansson says.

Source: Uppsala University

Categories : Ageing Cardiovascular DiseaseTags :

Oestrogen Pills may Increase Hypertension Risk

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Photo by cottonbro studio

Women ages 45 years and older taking oral oestrogen pills were more likely to develop hypertension than those using transdermal or vaginal formulations, according to new research published in Hypertension.

Less oestrogen and progesterone is produced in a woman’s body after menopause, which may increase the risk for cardiovascular diseases including heart failure, according to the American Heart Association.

Hormone therapy may be prescribed to relieve symptoms of menopause, in gender-affirming care and in contraception. Previous studies have found that some hormone therapies may reduce cardiovascular disease risk in menopausal women under 60 years of age or for whom it has been fewer than 10 years since menopause. The authors of this study noted that while hypertension is a modifiable risk factor for cardiovascular disease, the potential effects of different types of hormone therapy on blood pressure in menopausal women remain uncertain. 

“We know oestrogens ingested orally are metabolised through the liver, and this is associated with an increase in factors that can lead to higher blood pressure,” said lead study author Cindy Kalenga, an MD/PhD-candidate at the University of Calgary. 

“We know that post-menopausal women have increased risk of high blood pressure when compared to pre-menopausal women, furthermore, previous studies have shown that specific types of hormone therapy have been associated with higher rates of heart disease,” Kalenga said. “We chose to dive deeper into factors associated with hormone therapy, such as the route of administration (oral vs non-oral) and type of oestrogen, and how they may affect blood pressure.”

This study involved a large group of over 112 000 women, ages 45 years and older, who filled at least two consecutive prescriptions (a six-month cycle) for oestrogen-only hormone therapy, as identified from health administrative data in Alberta, Canada between 2008 and 2019. The main outcome of high blood pressure (hypertension) was identified via health records.

First, researchers investigated the relationship between route of oestrogen-only hormone therapy administration and risk of developing high blood pressure at least one year after starting the treatment. The 3 different routes of hormone therapy administration were oral (by mouth), transdermal and vaginal application. Additionally, researchers evaluated the formulation of oestrogen used and the risk of developing high blood pressure. For this study, the researchers reviewed medical records of individuals taking oestrogen-only hormone therapy. The two most common forms of oestrogen used by study participants were oestradiol – a synthetic form of oestrogen closest to the naturally produced form – and conjugated equine oestrogen, an animal-derived form of oestrogen and the oldest type of oestrogen therapy.

The analysis found:

  • Women taking oral oestrogen therapy had a 14% higher risk of developing high blood pressure compared to those using transdermal oestrogen and a 19% higher risk of developing high blood pressure compared to those using vaginal oestrogen creams or suppositories. After accounting for age, a stronger association was seen among women younger than 70 years of age compared to women older than 70.
  • Compared to estradiol, conjugated equine estrogen was associated with an 8% increased risk of developing high blood pressure.

Taking oestrogen for a longer period of time or taking a higher dose was associated with greater risk of high blood pressure, the authors noted. According to Kalenga, the study’s findings suggest that if menopausal woman take hormone therapy, there are different types of oestrogen that may have lower cardiovascular risks.

“These may include low-dose, non-oral oestrogen – like oestradiol, in transdermal or vaginal forms – for the shortest possible time period, based on individual symptoms and the risk–benefit ratio, Kalenga said. “These may also be associated with the lowest risk of hypertension. Of course, this must be balanced with the important benefits of hormone therapy, which include treatment of common menopausal symptoms.”

The average age of natural menopause among women worldwide is about 50 years of age. Current evidence supports that initiating menopausal hormone therapy in the early stages may have cardiovascular benefits, though not in the late stages of menopause, according to the American Heart Association’s 2020 Statement on Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention. Previous studies have found that menopausal hormone therapy may help relieve symptoms of menopause, including hot flashes, night sweats, mood changes or sleep disturbances.

Limitations included being based only on medical records, not including women younger than the age of 45 and not collecting data about hysterectomies or menopausal status (which was inferred by taking oestrogen after 45).

The authors will be conducting more research investigating combined oestrogen and progestin, as well as progestin-only formulations of hormone therapy and their impact on heart and kidney diseases.

Source: American Heart Association

Categories : CancerTags :

Oestrogen May Trigger Breast Cancer, Not Just Fuel it

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Breast cancer cells. Image by National Cancer Institute

In what could be a long-missing piece in the puzzle of breast cancer, researchers have identified the molecular sparkplug that ignites cases of the disease currently unexplained by the classical model of breast-cancer development. The team reported their work in Nature.

“We have identified what we believe is the original molecular trigger that initiates a cascade culminating in breast tumour development in a subset of breast cancers that are driven by oestrogen,” said study senior investigator Peter Park, Harvard Medical School professor.

The researchers said as many as one-third of breast cancer cases may arise through the newly identified mechanism.

The study also shows that the sex hormone oestrogen is the culprit behind this molecular dysfunction because it directly alters a cell’s DNA.

Most, though not all, breast cancers are fuelled by hormonal fluctuations. The prevailing view of oestrogen’s role in breast cancer is that it acts as a catalyst for cancer growth because it stimulates the division and proliferation of breast tissue, a process that carries the risk for cancer-causing mutations. The new work, however, shows that oestrogen causes mischief in a far more direct manner.

“Our work demonstrates that oestrogen can directly induce genomic rearrangements that lead to cancer, so its role in breast cancer development is both that of a catalyst and a cause,” said study first author Jake Lee.

While the findings does not have immediate therapy applications, it could lead to tests that can track treatment response and could help doctors detect the return of tumours in patients with a history of certain breast cancers.

Birth of a cancer cell

When DNA breaks in the process of cell division, the breaks usually get swiftly mended by the molecular machinery that guards the integrity of the genome. However, every now and then, the repair of broken DNA gets botched, causing chromosomes to get misplaced or scrambled inside a cell.

Many human cancers arise in this manner during cell division, when chromosomes get rearranged and awaken dormant cancer genes that can trigger tumour growth.

One such chromosomal scramble can occur when a chromosome breaks, and a second copy of the broken chromosome is made before the break gets fixed.

Then, in what ends up being a botched repair attempt, the broken end of one chromosome is fused to the broken end of its sister copy rather than to its original partner. The resulting new structure is a misshapen, malfunctioning chromosome.

During the next cell division, the misshapen chromosome is stretched between the two emerging daughter cells and the chromosome “bridge” breaks, leaving behind shattered fragments that contain cancer genes to multiply and get activated.

It has been known since the 1930s that certain human cancers, including some breast cancers, arise when a cell’s chromosomes get rearranged in this way. Cancer experts can often identify this particular aberration in tumour samples by using genomic sequencing. Yet, a portion of breast cancer cases do not harbour this mutational pattern, raising the question: What is causing these tumours?

These ‘cold’ intrigued study authors Park and Lee, who searched for answers by analysing the genomes of 780 breast cancers obtained from patients diagnosed with the disease. They expected to find the classical chromosomal disarray in most of the tumour samples, but many of the tumour cells bore no trace of this classic molecular pattern.

Instead of the classic misshapen and improperly patched-up single chromosome, they saw that two chromosomes had fused, suspiciously near ‘hot spots’ where cancer genes are located.

Just as in McClintock’s model, these rearranged chromosomes had formed bridges, except in this case, the bridge contained two different chromosomes. This distinctive pattern was present in one-third (244) of the tumours in their analysis.

Lee and Park realised they had stumbled upon a new mechanism by which a ‘disfigured’ chromosome is generated and then fractured to fuel the mysterious breast cancer cases.

A new role for oestrogen in breast cancer?

When the researchers zoomed onto the hot spots of cancer-gene activation, they noticed that these areas were curiously close to oestrogen-binding areas on the DNA.

Oestrogen receptors are known to bind to certain regions of the genome when a cell is stimulated by oestrogen. The researchers found that these oestrogen-binding sites were frequently next to the zones where the early DNA breaks took place.

This offered a strong clue that oestrogen might be somehow involved in the genomic reshuffling that gave rise to cancer-gene activation.

Lee and Park followed up on that clue by exposing breast cancer cells to oestrogen and then used CRISPR gene editing to make cuts to the cells’ DNA.

As the cells mended their broken DNA, they initiated a repair chain that resulted in the same genomic rearrangement Lee and Park had discovered in their genomic analyses.

Oestrogen is already known to fuel breast cancer growth by promoting the proliferation of breast cells. However, the new observations cast this hormone in a different light. They show oestrogen is a more central character in cancer genesis because it directly alters how cells repair their DNA.

The findings suggest that oestrogen-suppressing drugs such as tamoxifen work in a more direct manner than simply reducing breast cell proliferation.

“In light of our results, we propose that these drugs may also prevent oestrogen from initiating cancer-causing genomic rearrangements in the cells, in addition to suppressing mammary cell proliferation,” Lee said.

The study could lead to improved breast cancer testing. For instance, detecting the genomic fingerprint of the chromosome rearrangement could alert oncologists that a patient’s disease is coming back, Lee said.

A similar approach to track disease relapse and treatment response is already widely used in cancers that harbour critical chromosomal translocations, including certain types of leukaemia.

More broadly, the work underscores the value of DNA sequencing and careful data analysis in deepening the biology of cancer development, the researchers said.

“It all started with a single observation. We noticed that the complex pattern of mutations that we see in genome sequencing data cannot be explained by the textbook model,” Park said. “But now that we’ve put the jigsaw puzzle together, the patterns all make sense in light of the new model. This is immensely gratifying.”

Source: Harvard Medical School

Categories : Obstetrics & Gynaecology UrogenitalTags :

Oestrogen may Protect against Delirium in Older Women with UTIs

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Photo by Karolina Grabowska

Delirium is common among women with urinary tract infections (UTIs) – especially those who have experienced menopause. In mouse models, researchers have been able to prevent symptoms of the condition by administering oestrogen. Their study was published in the peer-reviewed journal Scientific Reports.

“There has been a resurgence of interest in hormone replacement therapy, and this study, which builds on our previous work, shows that it may be a tool to mitigate delirium,” said Shouri Lahiri, MD, director of the Neurosciences Critical Care Unit and Neurocritical Care Research at Cedars-Sinai and senior author of the study. “I think it is a major step toward a clinical trial of oestrogen in human patients with UTIs.”

Lahiri said that delirium is a common problem in older women with UTIs.

“Even as a medical student, you know that if an older woman comes to the hospital and she’s confused, one of the first things you check is whether the patient has a UTI,” Lahiri said.

In previous studies, Lahiri’s team found a connection between delirium and an immune-regulating protein called interleukin 6 (IL-6). Events such as lung injury or UTI cause IL-6 to travel through the blood to the brain, causing symptoms such as disorientation and confusion. Oestrogen is a known suppressor of IL-6, so the investigators designed experiments to test its effects on UTI-induced delirium.

The researchers compared pre- and postmenopausal mice with UTIs and observed their behaviour in several types of specialised environments. They found that the mice in which menopause had been induced exhibited symptoms of delirium, such as anxiousness and confusion, while the others did not.

When they treated the mice with oestrogen, levels of IL-6 in the blood and delirium-like behaviour were greatly reduced. The behavioural differences were not related to UTI severity, as bacterial levels in the urine weren’t markedly different between the two groups, Lahiri said.

The investigators also looked at the direct effects of oestrogen on neurons, using what Lahiri called a “UTI in a dish.”

“We exposed individual neurons to an IL-6 inflammation cocktail to create UTI-like injury,” Lahiri said. “But when we added oestrogen to the cocktail, it mitigated the injury. So, we showed that there are at least two ways that oestrogen helps reduce symptoms of delirium. It reduces IL-6 levels in the blood and protects the neurons directly.”

Just how oestrogen acts to protect neurons is still unexplained. And before conducting a clinical trial, researchers need to identify which patients with UTIs are most likely to experience delirium and at what point oestrogen treatment might be most effective.

“Currently, it is common practice to treat UTI-induced delirium using antibiotics, even though there are no clinical trials that indicate this practice is effective and it is not supported by clinical practice guidelines,” said Nancy Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “This work is an important step in determining whether modulating immune response via oestrogen replacement or other means is a more effective treatment.”

The team is also working to understand the different effects of delirium on females versus males, which was not a topic of this study. Effective treatment of delirium could be of long-term importance, Lahiri said, because it is a known risk factor for long-term cognitive impairments, such as Alzheimer’s disease and related dementia.

Source: Cedars-Sinai Medical Center

Categories : CancerTags :

Hormone Therapy does not Increase Breast Cancer Recurrence Risk in Survivors

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Research published in the Journal of the National Cancer Institute found that menopausal hormone therapy for breast cancer survivors is not associated with breast cancer reoccurrence, despite worries among some researchers and physicians.

Hot flashes and night sweats, as well as vaginal dryness and urinary tract infections, are common in breast cancer survivors, worsening quality of life and can lead patients to discontinue therapy. These symptoms may be alleviated by vaginal oestrogen therapy or menopausal hormone therapy (MHT). However, the safety of systemic and vaginal oestrogen use among breast cancer survivors, particularly those with oestrogen receptor-positive disease, has been unclear.

Many doctors caution breast cancer survivors against using MHT following the demonstration of an increased risk of breast cancer recurrence in two trials in the 1990s. Though later studies have not shown increased recurrence, they were seriously limited, with small sample sizes and short follow-up periods.

This study compared hormonal treatment with the risk of breast cancer recurrence and mortality in a large cohort of Danish postmenopausal women treated for early-stage oestrogen receptor-positive breast cancer.

Participants were diagnosed between 1997 and 2004 with early-stage breast cancer who received no treatment or five years of hormone therapy.

Among 8461 women, 1957 and 133 used vaginal oestrogen therapy or MHT, respectively, after diagnosis. No increase was seen in the risk of recurrence or mortality for those who received either vaginal oestrogen therapy or MHT.

“This large cohort study helps to inform the nuanced discussions between clinicians and breast cancer survivors about the safety of vaginal oestrogen therapy,” said Elizabeth Cathcart-Rake, writing in an accompanying editorial. “These results suggest that breast cancer survivors on tamoxifen with severe genitourinary symptoms can take vaginal estrogen therapy without experiencing an increase in their risk for breast cancer recurrence. However, caution is still advised when considering vaginal oestrogen for breast cancer survivors on aromatase inhibitors, or when considering menopausal hormonal therapy.”

Source: EurekAlert!

Categories : Cardiovascular Disease Metabolic DisordersTags :

In Diabetes, Oestrogen Protects Against Cardiomyopathy

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Source: Pixabay CC0

Oestrogen may protect diabetes patients from cardiomyopathy, according to research published in Circulation: Heart Failure. The study showed that severe insulin resistance in the heart causes cardiomyopathy and death in male mice, but also showed that oestrogen protected female mice.

“Cardiovascular disease is the major cause of morbidity and mortality for diabetic patients,” explained Shaodong Guo, PhD, primary investigator for the study at Texas A&M.

“Previous studies have shown that while there’s a lower instance of both cardiovascular disease and Type 2 diabetes in premenopausal women than in their age-matched male counterparts, these incidences rise sharply after female menopause,” Prof Guo said.

This indicates that the ovaries and ovarian hormones, such as oestrogen, may protect from Type 2 diabetes and cardiovascular diseases, he said.

The study investigated the role of ovaries and oestrogen in cardiac function and energy metabolism with mice who had the the cardiac insulin receptor substrate, IRS, modified or suppressed to mimic cardiac insulin resistance.

“Our previous studies reported that impaired cardiac insulin signalling with loss of insulin receptor substrate IRS1 and IRS2 genes leads to death of male mice,” he said. “In this study, we wanted to know how the removal of the ovaries might affect cardiomyopathy in female mice and also what other impacts the loss of insulin receptors might have on energy metabolism and mitochondrial function.” 

Insulin resistance and signaling

About 90–95% of patients with Type 2 diabetes suffer from insulin resistance, a risk factor for heart failure. In healthy tissue, insulin binds to insulin receptors, activating a network of intracellular signalling pathways. Disruptions in these signalling pathways have been linked to mitochondrial dysfunction, cardiomyopathy, and impaired glucose and fatty acid metabolism, among other health issues.

In this study, mice lacking IRS developed dilated cardiomyopathy, and analysis showed lowered activity of genes important for mitochondrial function and energy metabolism.

“Type 2 diabetes patients and insulin-resistant patients exhibit mitochondrial dysfunction,” Prof Guo explained.

The study fills in some blanks in understanding the role of insulin and estrogen signaling in mitochondrial function.

Study findings

Guo said there were four important findings from the study:

  • All female mice that lacked insulin receptor substrates survived for more than a year.
  • Female mice without insulin receptor substrates were less likely to experience severe cardiac dysfunction and death if they had ovaries. If the mice also lacked ovaries but received oestrogen, it prolonged their lifespans. Doses of oestrogen also protected IRS-altered male mice from heart dysfunction. 

Guo said oestrogen also prevents cardiomyopathy induced by loss of cardiac insulin receptor substrates.

“And removal of the ovaries leads to the death of female cardiac IRS1 and IRS2 double genes knockout mice if there is no reintroduction of oestrogen,” he said.

Loss of IRS1 and IRS2 genes in heart tissue disrupts cardiac energy metabolism, gene activity involved in mitochondrial function, and whole-body energy metabolism. However, oestrogen partially reverses these effects.

Oestrogen is important for healthy cellular signalling pathways and promotes mitochondrial function.

Prof Guo said the study shows that oestrogen enhances cardiac function, promotes energy metabolism, prevents cardiomyopathy and prolongs survival in both male and ovariectomy female mice lacking the insulin receptor substrates.  

“This study provides evidence for the gender difference for the incidence of cardiovascular disease and implies that oestrogen replacement therapy is feasible for the treatment of diabetic cardiomyopathy through enhancement of mitochondrial function and energy metabolism,” he said. “It also reveals some of the signalling pathways that may be potential therapeutic targets for the prevention or treatment of cardiovascular diseases in patients with Type 2 diabetes.” 

Guo also noted that diet could also play a role with oestrogens in foods.

“The study implies that food-derived oestrogens or phytoestrogens may play similar roles to oestrogen, as observed in mice,” he said. “This may help us reshape our knowledge of nutrient and food sciences related to plant hormones that can modulate chronic metabolic diseases such as Type 2 diabetes and associated cardiovascular complications.”

Source: Texas A&M University

Categories : COVIDTags :

Oestrogen from Hormone Replacement Therapy Reduces COVID Mortality

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Older woman smiling
Photo by Ravi Patel on Unsplasj

A new study in Family Practice reported that receiving oestrogen in the form of hormone replacement therapy within six months of a recorded diagnosis of COVID was associated with a reduction in mortality from the disease.

While men and women are equally susceptible to the infection, men tend to have more severe disease, with higher rates of hospitalisation and mortality. A recent 38-country review of sex differences in COVID found men to have a 1.7 times higher mortality rate than women. Younger women or those with higher oestrogen levels are less likely to experience COVID complications.

Earlier studies have also shown that women have faster and greater immune responses to viral infections. Similar trends has been observed in previous pandemics, including the SARS-CoV (Severe Acute Respiratory Syndrome Corona Virus) and MERS-CoV (Middle East Respiratory Syndrome Corona Virus) outbreaks.

The reason for these sex differences is uncertain. Limited recent observational data suggest that oestrogen may reduce the severity of COVID disease. This study investigated the association between hormone replacement therapy or combined oral contraception use, and the likelihood of death in women with COVID. Researchers investigated combined oral contraception, which contains oestrogen, because some Recent observational data suggests that women taking oral contraceptives have a lower risk of acquiring COVID.

Investigators used a retrospective cohort with medical records from the Oxford-Royal College of General Practitioners Research and Surveillance Centre primary care database. They identified a group of 1 863 478 women over 18 from 465 general practices in England.  There were 5451 COVID cases within the cohort. Hormone replacement therapy was associated with a 22% reduction in all-cause mortality in COVID.

This suggests that oestrogen may well contribute a protective effect against COVID severity. This may explain why fewer women compared to men have been hospitalised, admitted to ICU, or died due to COVID during the pandemic.

“This study supports the theory that oestrogen may offer some protection against severe COVID,” said Christopher Wilcox, one of the paper’s authors. “We hope that this study can provide reassurance to patients and clinicians that there is no indication to stop hormone replacement therapy because of the pandemic.”

Source: EurekAlert!