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Hormonal health

FDA plans to revise black box warning on menopause hormone therapies

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The US Food and Drug Administration (FDA) plans to update the black box warning on menopause hormone therapies soon, commissioner Dr Martin Makary has said.

The move follows years of debate over safety alerts that have limited access to treatment for millions of women with menopause symptoms.

“We are in serious discussions now about what to do about the black box warning, and I think you’ll hear something on it very soon,” Makary told CNN’s Dr Sanjay Gupta on the Chasing Life podcast.

The black box warning – the FDA’s strongest safety alert – has appeared on oestrogen-containing menopause treatments since 2003, including pills, patches, sprays and creams.

It warns that their use can increase the risk of uterine and breast cancers, strokes, blood clots and dementia in women over 65.

The label was added after a large government-funded study found that women taking oestrogen pills after menopause had higher risks for certain cancers, heart disease and stroke compared with those given a placebo.

The participants had an average age of 63, meaning many were already past menopause when they began therapy.

After the study and label change, prescriptions for hormone replacement therapy (HRT) dropped by more than 70 per cent, and many doctors became reluctant to prescribe them.

“It’s really a tragedy. It’s maybe one of the greatest screw-ups of modern medicine,” Makary said.

“It’s resulted in 50 million women being denied this incredible therapy.”

The result has been undertreatment of symptoms that can be debilitating for women in midlife.

In the late 1990s, more than one in four postmenopausal women took hormones to manage symptoms such as hot flushes (sudden sensations of heat), mood swings and night sweats.

By 2020, that figure had dropped to about one in 25.

Newer analyses of the original Women’s Health Initiative data have since found that hormone therapy started in women under 60, or within 10 years of starting menopause, may safely help manage symptoms such as hot flushes and poor sleep, provided they do not have specific contraindications such as a history of hormone-sensitive breast or uterine cancer.

Makary said HRT may also have benefits including reducing bone loss, lowering heart disease risk and helping preserve memory.

“Women live longer and feel better on hormone replacement therapy when started before age 60,” Makary told Gupta.

The potential change follows a July meeting of experts convened by the FDA to discuss the benefits and risks of hormone replacement therapy.

The panellists urged the agency to remove the warning label.

“I am begging the FDA, and all of us are begging, please remove the box label,” said Dr JoAnn Pinkerton, professor of obstetrics and gynaecology at the University of Virginia School of Medicine.

“And please stop harming women.”

Some women’s health experts say the FDA overstepped when it applied the boxed warning to all forms of oestrogen replacement.

“That is a real mistake,” said Dr JoAnn Manson, professor at Harvard Medical School and one of the principal investigators of the Women’s Health Initiative study.

Some forms do not raise oestrogen levels in the blood, so they are unlikely to increase cancer risk.

For example, studies have found that low doses of oestrogen delivered by vaginal tablets, creams or rings can safely treat symptoms of dryness, painful sex and urinary tract infections in postmenopausal women, Manson said.

However, the black box warning may still deter women from using them.

“It scares them away. And even after they purchase the product, they just don’t take it,” Manson said.

“This is really where women are being tremendously undertreated and are suffering unnecessarily due to a boxed warning that is just class labelling.

“All hormone therapy products get exactly the same boxed warning, and it is really harming women,” said Manson, who is chief of the Division of Preventive Medicine at Brigham and Women’s Hospital.

Manson said it would also be reasonable for the FDA to consider removing the warnings from oestrogen-containing therapies delivered through the skin in patches, sprays or creams to relieve menopause symptoms such as hot flushes and night sweats.

These deliver hormones into the bloodstream, but observational studies suggest they have a more favourable balance of risks and benefits than pills.

She was less certain about removing the boxed warning from oestrogen-containing pills taken by mouth.

“I think that’s where it’s evidence-based and justified,” she said.

A 2022 review by the US Preventive Services Task Force concluded that, in women past menopause, there was no net benefit to taking either oestrogen alone – prescribed for women who have had their uterus removed – or a combination of oestrogen and progestin – typically prescribed for women who still have their uterus – to prevent chronic conditions such as heart disease and dementia.

What remains unclear is whether women who start hormone therapy during perimenopause (the transition before menopause) need to stay on it long-term to gain potential heart, brain and bone benefits.

“It’s a very good question,” said Dr Roberta Diaz Brinton, a neuroscientist who studies oestrogen’s effects on the brain at the University of Arizona.

“We need to answer that.”

Other experts say there is still not enough scientific evidence to support long-term use of hormones to prevent heart disease, Alzheimer’s disease or osteoporosis.

Four medical societies – the American College of Obstetricians and Gynecologists, the Menopause Society, the Endocrine Society and the American Association of Clinical Endocrinology – support the use of hormones to relieve menopausal symptoms but do not recommend continued use to prevent chronic conditions such as heart disease.

Dr Leslie Cho, who runs Cleveland Clinic’s women’s cardiovascular centre, said she supports lifting the warning from vaginal oestrogen cream.

“It’s never made sense on the cream,” she said.

But Cho warned that some of the proposed benefits are based on after-the-fact analyses of studies that were not designed to measure them.

“I’m so glad to hear the FDA chair talk about this, because then, if that’s the case, they should do a study.

“They should fund a study,” she said.

With the rise of online hormone prescriptions, Cho warned that some women could start taking hormones despite having risk factors such as high blood pressure, obesity or high cholesterol, which could outweigh potential benefits.

Even in younger women, studies show that hormones may increase the risk of blood clots.

“Women have to talk to their physicians about hormone replacement therapy before they believe in all the hype that’s currently ongoing, because so much of it is hype,” she said.

Insight

PCOS renamed after decade-long campaign to end ‘cyst’ misconception

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After more than a decade of campaigning, doctors around the world have agreed to rename polycystic ovary syndrome (PCOS).

It is hoped the new name, polyendocrine metabolic ovarian syndrome, or PMOS, will help end the misconception that the condition is all about cysts, which campaigners say has contributed to missed diagnoses and inadequate treatment.

The condition affects one in eight women, or 3.1m women and girls in the UK, and is linked to hormone fluctuations that can affect weight, mental health, skin and the reproductive system.

The renaming was spearheaded by UK patient charity Verity alongside Professor Helena Teede, director of Melbourne’s Monash Centre for Health Research and Implementation.

It followed 14 years of consultation with clinicians and patients around the world.

The new name was published in a consensus statement on May 12 and announced at the European Congress of Endocrinology in Prague.

The paper states that PCOS should now be referred to as PMOS.

“This is a landmark moment that will lead to desperately-needed worldwide advancements in clinical practice and research,” said Professor Teede.

“It was heart-breaking to see the delayed diagnosis, limited awareness and inadequate care afforded those affected by this neglected condition.”

When doctors first named PCOS in 1935, they thought it was mainly caused by physical changes to the ovaries.

Decades of research have since changed that understanding, with clinicians now agreeing the condition is far more complex.

“What we now know is that there is actually no increase in abnormal cysts on the ovary and the diverse features of the condition were often unappreciated,” Professor Teede added.

“A name change was the next critical step towards recognition and improvement in the long term impacts of this condition.”

The exact cause of the condition is still unknown, though it is thought to be linked to abnormal hormone levels and is associated with insulin resistance and raised levels of testosterone and luteinising hormone.

Insulin resistance means the body does not respond properly to insulin, the hormone that helps control blood sugar. Luteinising hormone helps regulate ovulation.

Common symptoms listed by the NHS include irregular periods or no periods at all, difficulty getting pregnant, excessive hair growth, weight gain, thinning hair, oily skin and acne.

Campaigners have acknowledged that the name change could cause temporary confusion.

“Despite decades of tireless advocacy to improve awareness, we recognised that the risk of change would be worth the reward,” said Rachel Morman, chairwoman of Verity.

“This shift will reframe the conversation and demand that it is taken as seriously as the long-term, complex health condition it is.”

It is also unclear if, or when, the NHS will change the language it uses.

An NHS England spokesperson said: “We routinely review and update content on the NHS website to ensure it reflects the latest clinical advice and will carefully consider these recommendations.

“The NHS will also continue our work to improve women’s healthcare, including for this important group, which involves giving women more choice over their care, bringing down waiting times, and delivering more care in communities.”

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Hormonal health

Tampons could track MS nerve damage, study suggests

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Menstrual fluid collected from tampons could one day provide a simple, non-invasive way to measure a biomarker of nerve damage and potentially track disease activity in neurological conditions such as multiple sclerosis (MS), new research suggests.

Because neurofilament light chain, or NfL, has emerged as a promising biomarker of MS, detecting it in menstrual fluid raises the possibility of monitoring disease activity through the natural monthly cycle of menstruation.

Researchers at Nextgen Jane, in collaboration with Siemens Healthineers, found that NfL, a protein released when nerve cells are damaged, can be reliably detected in tampon-collected menstrual samples.

“Finding that NfL tracks with estrogen levels in menstrual fluid, independent of how much blood is in the sample, tells us there is real biology here, not just contamination,” said Ridhi Tariyal, chief executive and co-founder of Nextgen Jane.

“That changes what this specimen means for neurology.”

In MS, the immune system mistakenly attacks healthy parts of the brain and spinal cord, causing inflammation and damage that can lead to symptoms such as fatigue, numbness, muscle weakness, and problems with balance or vision.

Confirming a diagnosis of MS usually requires a combination of physical and neurological examinations, MRI scans to check for brain and spinal cord damage, and lab tests.

These can include detecting certain proteins in cerebrospinal fluid, the fluid that surrounds the brain and spinal cord, which may indicate inflammation in the brain or spinal cord.

After diagnosis, patients are usually monitored through clinical assessments and routine MRI scans, which help doctors detect changes in disease activity and determine whether treatments are working.

However, MRI assessments can be costly and are usually done once or twice a year, which can prevent doctors from spotting early changes and making timely treatment adjustments.

Because of these challenges, researchers have long sought cost-effective, more accessible biomarkers that could help detect MS earlier, monitor disease activity over time, and evaluate treatment response.

One of the most promising candidates is NfL, a protein found in nerve cell fibres that is released into the bloodstream and cerebrospinal fluid when nerve cells are injured.

To explore whether menstrual fluid could serve as a source for detecting this biomarker and, more broadly, as a non-invasive specimen for monitoring neurological, hormonal and inflammatory signals, researchers analysed 99 tampon-collected menstrual fluid samples from 91 participants.

They used Siemens Healthineers’ highly sensitive NfL assay on its automated testing platform. The team also measured hormonal and inflammatory molecules.

NfL was detected in 98 of the 99 menstrual fluid samples analysed, suggesting the biomarker can be reliably measured in tampon-collected samples.

The researchers also found that NfL levels were associated with estradiol levels, a form of the hormone oestrogen, and that this relationship remained significant even after adjusting for differences in blood content between samples.

By comparison, levels of inflammatory markers were more strongly linked to blood content itself.

According to the researchers, this suggests NfL detection was not merely the result of blood contamination, but may reflect biologically meaningful changes that could potentially be tracked over time through routine menstrual sampling.

Building on these findings, Nextgen Jane is now planning prospective studies to investigate whether menstrual NfL and other neurological proteins can be used to track disease activity over time in conditions such as MS.

“The menstrual cycle provides a built-in longitudinal framework: the same individual, the same biological process, month after month,” said Stephen Gire, chief scientific officer at Nextgen Jane.

“Coupling the NextGen Jane platform with Siemens Healthineers’ highly sensitive NfL assay gives us a path to study neurological biomarker trajectories in a way that has not been possibe before.”

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Fertility

Toxins and climate harms having ‘alarming’ effect on fertility, research warns

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Simultaneous exposure to toxic chemicals and climate-related heat may be worsening fertility harms across humans and wildlife, research suggests.

The review of scientific literature looks at how endocrine-disrupting chemicals, often found in plastic, together with climate-related effects such as heat stress, are each linked to lower fertility and fecundity, meaning the ability to reproduce, across species including humans, wildlife and invertebrates.

Though the reproductive harms of each issue in isolation are well studied, there is little research on what happens when living organisms are exposed to both.

“Together, the two issues are likely to pose a greater threat to fertility, and the additive effect is “alarming”, said Susanne Brander, a study lead author and courtesy faculty at Oregon State University.

“You’re not just getting exposed to one, but two, stressors at the same time that both may affect your fertility, and in turn the overall impact is going to be a bit worse,” Brander said.

The paper looked at 177 studies.

Shanna Swan, a co-author on the new paper, co-produced a 2017 study that found sperm levels among men in western countries had fallen by more than 50 per cent over four decades. Other research has suggested human fertility has been declining at a similar rate.

The University of Washington’s Institute for Health Metrics and Evaluation has previously said the world was approaching a “low-fertility future”, with more than three quarters of countries below replacement rate by 2050.

The new paper’s authors focused on the effects of endocrine-disrupting chemicals and substances, including microplastics, bisphenol, phthalates and PFAS.

These are thought to cause a range of serious reproductive problems, disrupt hormones and be a potential driver of falling fertility.

Brander said the harms linked to these chemicals are often similar across organisms, from invertebrates to humans.

Phthalates, for example, have been linked to altered sperm shape in invertebrates, spermatogenesis in rodents, meaning sperm production, and reduced sperm counts in humans.

PFAS are also thought to affect sperm quality, and both have been linked to hormone disruption.

The chemicals are widespread in consumer goods, so people are often regularly exposed.

Meanwhile, previous research has shown how rising temperatures, lower oxygen levels and heat stress, among other effects linked to climate change, may also worsen infertility.

Heat stress has been found to affect human hormones, and is linked to spermatogenesis in rodents and bulls.

Research shows temperature also plays a role in sex determination in fish, reptiles and amphibians.

The species has evolved to choose which sex it produces in part based on temperature, and the heating planet can “push it too far in one direction or the other, which overrides that evolutionary benefit”, Brander said.

Similarly, many endocrine disruptors may alter environmental sex determination.

The study set out some of the overlapping effects of chemical exposure and climate change across taxonomic groups, from invertebrates to humans.

In birds, for example, exposure to increased temperature, PFAS, organochlorines and pyrethroids may each individually cause abnormal sperm, increased fledgling mortality, abnormal testes and population decline.

“What happens if they’re exposed to more than one of those stressors at the same time? There has been little exploration of that question.

“Even if there have not been a lot of studies looking at these simultaneously, if you have two different factors that both cause the same adverse effect, then there’s a likelihood that they are going to be additive,” Brander said.

Katie Pelch, a senior scientist with the Natural Resources Defense Council nonprofit, who was not part of the study, said the authors had reviewed high-quality science.

She said she wanted to see more examples of the overlap in impacts, but agreed with the overall premise.

“It is likely [multiple stressors] would have an additive effect, at very least, even if they have different mechanisms of harm,” Pelch added.

The solution to the systemic problems would involve tackling climate change and reducing the use of toxic chemicals.

The study cites the global reduction in the use of DDT and PCBs achieved under the Stockholm Convention as an example of an effective measure, but Brander said much more is needed.

“There is enough evidence in both areas to act to reduce our impact on the planet,” she said.

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