Monthly Archives: September 2019

Hormone diets are all the rage, but do they actually work?

There’s currently no peer-reviewed research published in any major scientific journals backing up the hormone diet’s claims. Shutterstock/Gts

Hormone diets are all the rage, but do they actually work?

September 23, 2019 7.28pm AEST


  1. Robert Naughton Senior Lecturer, University of Huddersfield

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When it comes to losing weight and getting healthy, there is never a shortage of diet and fitness crazes claiming to hold the secret to easy, sustainable weight loss. Some of the most recent popular diet crazes include the ketogenic diet (low carbohydrate, high fat), the carnivore diet (only eating meat and other animal products), and intermittent fasting (eating only within a strict timeframe or on certain days).

But another diet plan that’s come into the spotlight recently is the hormone diet, which claims that the reason people struggle to lose weight is because their hormones aren’t working properly.

Many books have been written on this topic, with advocates of the hormone diet claiming people can quickly lose a significant amount of weight by using diet and exercise to manipulate or “reset” their hormones. There are a few variations of the diet, but the main idea with each is that the key to losing weight is by correcting perceived hormonal imbalances in the body.

Hormones play an important role in our body’s everyday processes, from digesting food to helping bones grow. They’re transported around the body through the bloodstream and act as “chemical messengers” that instruct cells to perform specific jobs.

For example, insulin is essential for regulating metabolic processes and allows the body to store the carbohydrates from food as energy in our muscle cells. When we eat, it causes blood sugar levels to rise, which results in the pancreas releasing insulin into the bloodstream. The insulin then attaches itself to cells and signals them to absorb sugar from the bloodstream and store it for later use.

Insulin was once thought to play a key role in weight gain, but recent research shows that total calorie intake is the primary factor in gaining or losing weight. Fat loss can only be achieved by creating a calorie deficit, which simply means that you must burn more calories than you consume. Similarly, this is why many people have success with intermittent fasting, as it typically results in people eating less food and therefore fewer calories.

The hormone diet claims healthy eating and exercise are key to ‘resetting’ your hormones. ezphoto/Shutterstock

One popular book promoting the hormone diet uses a three-step programme that claims it will help people lose weight, gain strength, and feel younger. Steps one and two of the diet focus on changing nutritional habits. Step three concentrates on exercise.

According to the author, readers must “detox” their body. In step one, readers remove foods such as alcohol, caffeine, sugar, red meat, cow’s milk and milk byproducts (such as cheese or yoghurts) from their diet, while simultaneously eating more fruits and vegetables, poultry, fish, eggs, dairy products from sheep and goats, and plant milks. In step two, readers must then cut out processed foods, artificial sweeteners and refined grains. Step three involves an increase in cardiovascular and strength exercises.

The dietary recommendations provided in steps one and two require a decrease in food products that are typically high in calories and low in nutritional value, such as alcohol, high-sugar foods and processed foods. The diet also promotes foods such as vegetables, fish and fruit, which increase fibre intake (important for the digestive system) and provides the body with a variety of vitamins and minerals that perform many bodily functions needed for overall health and well-being. These foods are also generally lower in calories than alcohol, high-sugar foods and processed foods. And paired with the recommended exercises in step three, this “hormone diet” will probably increase calorie “burning” along with other health benefits.

Does the ‘hormone diet’ work?

Generally, the hormone diet recommended in this book is not bad nutritional advice. But the key here is that any potential weight loss will probably be from the change in calorie intake, rather than an effect (if any) on your hormones.

Weight loss (or body fat loss) is achieved by creating a calorie deficit, not by “resetting your hormone balance”. Despite what advocates of the hormone diet might claim, hormonal imbalances are usually the result of a more serious underlying health condition, such as diabetes (impaired insulin function) or hyperthyroidism (where the thyroid produces too many thyroid hormones), which couldn’t simply be fixed through diet alone, and would require medical treatment.

Read more: The science behind diet trends like mono, charcoal detox, Noom and Fast800

Currently, there is no viable theory to demonstrate that a person can “reset” their hormones to influence fat loss. There is also no peer-reviewed research in a major journal that has specifically studied the hormone diet and its effects. But there might be a simple explanation for why people think the hormone diet works: it helps to create a calorie deficit through improved nutritional habits and exercise, which will probably result in weight loss.

Ultimately, anyone that wants to lose weight or body fat should focus on creating a calorie deficit. How a person creates this calorie deficit may vary from person to person, and might even include following popular diet plans like keto or intermittent fasting. However, the best approach is whichever someone finds the most compatible with their lifestyle.

I have painful periods, could it be endometriosis?

I have painful periods, could it be endometriosis?

Endometriosis can cause a number of symptoms, including pain during sex and pelvic pain outside of the period cycle. Jon Ly

Nine in ten young women experience the cramping or stabbing of period pain just before their monthly bleed or as it starts.

Period pain (also called dysmenorrhoea) can be divided into two main types – primary or secondary dysmenorrhoea – depending on whether there’s an underlying problem.

Primary dysmenorrhoea occurs in women with normal pelvic anatomy. It’s due, at least in part, to changes in hormone-like compounds called prostaglandins. Too much of a prostaglandin called PGF2a causes the uterus to contract.

Secondary dysmenorrhoea is period pain that is caused by underlying pelvic problem and the most common cause is endometriosis. Endometriosis occurs when tissue similar to the lining of the uterus (the endometrium) is found outside the uterus.

Read more: Endometriosis is more than just a ‘women’s problem’

Period pain is common

Endometriosis can cause a number of severe symptoms, including period pain. But painful periods alone, even if they are bad, aren’t a surefire indicator of endometriosis.

Of the 90% of young women in Australia who experience period pain, most will have symptoms suggestive of primary, rather than secondary, dysmenorrhoea.

The exact number of women with endometriosis is still unclear but estimates suggest between 5% and 10% of reproductive-aged women have endometriosis.

So, most young women with period pain are likely to have primary dysmenorrhoea rather than endometriosis.

When does it start?

Primary dysmenorrhoea usually starts within the first three years after the first period and tends to get less severe with age.

Some women with endometriosis have pain that starts with or soon after their first period, while some women with endoemtriosis have relatively “normal” periods and their pain gets much worse after 18.

Pain can start with a girl’s first period. Jeffrey Lin

Period pain

Women tend to describe period pain from primary dysmenorrhoea as “cramping”, but it’s different for each woman. It can also feel stabbing or sharp; women with endometriosis use similar descriptions.

Pain from primary dysmenorrhoea can range from very mild to quite severe, while moderate to severe period pain is one of the most common symptoms women with endometriosis experience, regardless of their age.

Read more: Health Check: are painful periods normal?

Pain outside the period

One type of pain that isn’t common in primary dysmenorrhoea is “non-cyclical” or “acyclical” pelvic pain: pain below your belly button that occurs on a regular basis when you are not having your period. It might not be every day but commonly at least a couple of times per week.

Non-cyclical pelvic pain is very common in women with endometriosis, especially among young women but isn’t commonly associated with primary dysmenorrhoea.

Bowel and bladder pain or dysfunction

Bowel and bladder pain are common symptoms of endometriosis, and symptoms can vary greatly. Some women report bowel and/or bladder pain during their period, while others experience the pain outside of their period.

More than half of women with endometriosis urinate more often and many experience pain with urination on a regular basis.

Bowel changes can mimic symptoms of irritable bowel syndrome, including more or less frequent bowel movements, and harder stools or diarrhoea.

Painful sex

Women with endometriosis are nine times more likely to experience painful sex (dyspareunia) than women without endometriosis. This is usually described as “deep dyspareunia” – pain occurring high in the vagina and usually associated with thrusting.

Many women also experience burning pain after intercourse, which can last for hours or days.

Managing primary dysmenorrhoea

Non-steroidal anti-inflammatories (such as ibuprofen) and the oral contraceptive pill are common treatments for primary dysmenorrhea and can be very effective when taken correctly.

Read more: What happens to endometriosis when you’re on the pill?

There is also evidence heat and other physical activities such as yoga and stretching can reduce primary dysmenorrhoea symptoms.

So do I have endometriosis?

If your period pain is mild and occurs just prior to or during your period, and it doesn’t cause you to miss work or school, then your risk of endometriosis is low. But it’s important to note not all women with endometriosis will have symptoms. In asymptomatic women, endometriosis is often only diagnosed when they encounter fertility issues.

Endometriosis doesn’t always cause pain. Rawpixel

Women with endometriosis are more likely to exhibit the symptoms detailed above, but having one or all of these symptoms is not definitive for a diagnosis of endometriosis. The formal diagnosis of endometriosis is made using laparoscopy, where a small camera is inserted into the pelvic/abdominal cavity looking for endometriosis lesions.

There are other causes for some or all of these symptoms, including adenomyosis (where cells grow in the muscle of the uterus), uterine fibroids (non-cancerous growths in the wall of the uterus), vulvodynia (vulvar pain which doesn’t have a clear cause) and irritable bowel syndrome (which affects the functioning of the bowel).

Read more: Can diet improve the symptoms of endometriosis? Sadly, there’s no clear answer

When do I need to speak to my doctor?

If you have any of the following, it’s worth getting in touch with your doctor:

  • regular non-cyclical pelvic pain, pain during sex, or pain related to your bladder or bowel motions
  • period pain that doesn’t respond well to ibuprofen or the pill, and you’re still in enough pain to prevent you from going to work or school
  • sudden onset of severe period pain, or a significant worsening, after the age of 18
  • changes in your cycle, such as bleeding more than normal or at unusual times
  • symptoms that interfere with your ability to do normal things like go to school or work
  • pain or other symptoms, plus a mum or sister who has endometriosis (research suggests you are at higher risk of having endometriosis yourself).

Or, if you just feel like there is something wrong, go and speak to your GP or gynaecologist. They will be able to discuss options for further investigations and treatment.

LDN and Chronic Pain.


By now you should know that I am keen on the use of LDN for a wide range of problems, especially autoimmune diseases and pain problems, like fibromyalgia. The results have generally been good, but we have to careful about not over hyping the treatment, as it is not a miracle treatment (though for some it is). This article from the mainstream media (National Public Radio – NPR) in the USA is interesting. I know of some specialists who are now using LDN so it appears to be catching on – slowly.

In Tiny Doses, An Addiction Medication Moonlights As A Treatment For Chronic Pain

September 23, 20194:02 PM ET Heard on All Things Considered

Alex Smith

KCUR 89.3


Lori Pinkley of Kansas City, Mo., has struggled with chronic pain since she was a teenager. She has found relief from low doses of naltrexone, a drug that at higher doses is used to treat addiction. Alex Smith/KCUR

Lori Pinkley, a 50-year-old from Kansas City, Mo., has struggled with puzzling chronic pain since she was 15.

She’s had endless disappointing visits with doctors. Some said they couldn’t help her. Others diagnosed her with everything from fibromyalgia to lipedema to the rare Ehlers-Danlos syndrome.

Pinkley has taken opioids a few times after surgeries but says they never helped her underlying pain.

“I hate opioids with a passion,” Pinkley says. “An absolute passion.”

Recently, she joined a growing group of patients using an outside-the-box remedy: naltrexone. It is usually used to treat addiction,in a pill form for alcohol and as a pill or a monthly shot for opioids.

Poll: Nearly 1 in 5 Americans Says Pain Often Interferes With Daily Life

As the medical establishment tries to do a huge U-turn after two disastrous decades of pushing long-term opioid use for chronic pain, scientists have been struggling to develop safe, effective alternatives.

When naltrexone is used to treat addiction in pill form, it’s prescribed at 50 mg, but chronic-pain patients say it helps their pain at doses of less than a tenth of that.

Low-dose naltrexone has lurked for years on the fringes of medicine, but its zealous advocates worry that it may be stuck there. Naltrexone, which can be produced generically,is not even manufactured at the low doses that seem to be best for pain patients.

Instead, patients go to compounding pharmacies or resort to DIY methods — YouTube videos and online support groups show people how to turn 50 mg pills into a low liquid dose.

Some doctors prescribe it off-label even though it’s not FDA-approved for pain.

University of Kansas pain specialist Dr. Andrea Nicol has recently started prescribing it to her patients, including Pinkley. Nicol explains that for addiction patients, it works by blocking opioid receptors — some of the brain’s most important feel-good regions. So it prevents patients from feeling high and can help patients resist cravings.

At low doses of about 4.5 mgs, however, naltrexone seems to work completely differently.

“What it’s felt to do is not shut down the system, but restore some balance to the opioid system,” Nicol says.

How To Teach Future Doctors About Pain In The Midst Of The Opioid Crisis

Some of the hype over low-dose naltrexone has included some pretty extreme claims with limited research to back them, like using it to treat multiple sclerosis and neuropathic pain or even using it as a weight-loss drug.

In the past two years, however, there’s been a big increase in new studies published on low-dose naltrexone, many strengthening its claims as a treatment for chronic pain, though most of these were still small pilot studies.

Dr. Bruce Vrooman, an associate professor at Dartmouth’s Geisel School of Medicine, was an author of a recent review of low-dose naltrexone research. Vrooman says that when it comes to treating some patients with complex chronic pain, low-dose naltrexone appears to be more effective and well-tolerated than the big-name opioids that dominated pain management for decades.

“Those patients may report that this is indeed a game changer,” Vrooman says. “It may truly help them with their activities, help them feel better.”

So how does it work? Scientists think that for many chronic pain patients, the central nervous system gets overworked and agitated. Pain signals fire in an out-of-control feedback loop that drowns out the body’s natural pain-relieving systems.

They suspect that low doses of naltrexone dampen that inflammation and kick-start the body’s production of pain-killing endorphins — all with relatively minor side effects.

Despite the promise of low-dose naltrexone, its advocates say few doctors know about it.

The low-dose version is generally not covered by insurance, so patients typically have to pay out of pocket to have it specially made at compounding pharmacies.

Exercising To Ease Pain: Taking Brisk Walks Can Help

Advocates worry that the treatment is doomed to be stuck on the periphery of medicine because, as a 50-year-old drug, naltrexone can be made generically.

Patricia Danzon, a professor of health care management at the Wharton School at the University of Pennsylvania, explains that drug companies don’t have much interest in producing a new drug unless they can be the only maker of it.

“Bringing a new drug to market requires getting FDA approval and that requires doing clinical trials,” Danzon says. “That’s a significant investment, and companies — unsurprisingly — are not willing to do that unless they can get a patent and be the sole supplier of that drug for at least some period of time.”

And without a drug company’s backing, a treatment like low-dose naltrexone is unlikely to get the big promotional push out to doctors and TV advertisements that have turned drugs like Humira or Chantix into household names.

“It’s absolutely true that once a product becomes generic, you don’t see promotion happening, because it never pays a generic company to promote something if there are multiple versions of it available and they can’t be sure that they’ll capture the reward on that promotion,” Danzon says.

The drugmaker Alkermes has had huge success with its exclusive rights to the extended-release version of naltrexone, called Vivitrol. In a statement for this story, the company says it hasn’t seen enough evidence to support the use of low-dose naltrexone to treat chronic pain and therefore is remaining focused on opioid addiction treatment.

Pinkley says she is frustrated that there are so many missing pieces in the puzzle of understanding and treating chronic pain, but she, too, has become a believer in naltrexone.

She has been taking it for about a year now, at first paying $50 a month out of pocket to have the prescription filled at a compounding pharmacy. In July, her insurance started covering it.

“I can go from having days that I really don’t want to get out of bed because I hurt so bad,” she says, “to within a half-hour of taking it, I’m up and running, moving around, on the computer, able to do stuff.”

This story is part of NPR’s reporting project with KCUR and Kaiser Health News.

Sugars in mother’s milk help shape baby’s microbiome and ward off infection

Sugars in mother’s milk help shape baby’s microbiome and ward off infection

While living in a mother’s womb, cushioned by amniotic fluid and protected from the outside world, babies have only minimal exposure to microorganisms like bacteria and viruses. Shortly after birth, a newborn’s collection of microorganisms – their microbiome – begins to develop as a succession of bacteria colonizes their gut.

A variety of factors, such as mode of delivery (cesarean or vaginal birth) and antibiotic use, influence this population of bacteria. After that, human milk serves as a primary way more bacteria are introduced to a baby’s system, as it can contain up to 700 different species of bacteria.

In my research as a chemist, I’ve been focusing on the complex sugars that human milk contains. My colleagues and I are interested in how these sugar molecules help mold a baby’s microbiome and contribute to overall health. Ultimately we hope that knowing more about individual molecules in human breast milk will lead to the development of better infant formulas that can be used in cases where breastfeeding isn’t possible.

What’s in mother’s milk

You’ve probably heard that breast milk provides all the energy requirements, vitamins and nutrients that an infant needs. In fact, the World Health Organization recommends exclusively breastfeeding babies for the first six months of life when possible. Unfortunately there are a number of reasons that breastfeeding can be a challenge to keep up; and indeed, only about a quarter of American babies meet that guideline.

Breastmilk has a number of health benefits, beyond just keeping a baby well-fed. Exclusively breastfed babies have lower infant mortality due to common childhood illnesses such as diarrhea, pneumonia, urinary tract infection, ear infection, necrotizing enterocolitis and sudden infant death syndrome (SIDS), compared to formula-fed counterparts. And antibodies in milk mean breastfeeding helps babies recover quicker when they do fall ill.

Researchers know human milk contains two types of simple proteins, whey and casein, which are easily digested. It also has complex proteins including lactoferrin, which inhibits the growth of iron-dependent bacteria, and secretory IgA, which protects the infant from viruses and pathogenic bacteria. It provides a number of essential fats that are necessary for brain development, vitamin absorption and nervous system development.

And then there are the complex sugars called human milk oligosaccharides or HMOs that have long been neglected by the scientific community. As trained organic chemists, my team took an interest in HMOs precisely because not much was known about them. A few studies had found that these sugars were food for good bacteria, but not the pathogenic ones. It seemed like there must be more to the story. We also knew we’d be able to synthesize in the lab any molecules we identified as important.

Basic techniques of organic chemistry can isolate the sugars from a mother’s milk. Steven Townsend, CC BY-ND

A closer look at mom’s milk sugars

These complex sugars in human milk appear to provide a growth advantage for good bacteria. For example, breastfed infants have a microbiome rich in two species of bacteria: Bacteroides and Bifidobacteria. Both species are symbiotes, meaning they live with us on a daily basis, but typically cause no harm. They live in the human gut where they use human milk oligosaccharides as energy sources to grow, whereas pathogens do not. Breastfed babies tend to be colonized to a lesser extent by infectious species, meaning they get sick less.

Many of the protective properties of human milk have been attributed to its HMO component. For instance, research has shown that HMO supplementation shortens the duration of rotavirus infection – one of the leading causes of diarrhea in infants.

Bovine milk, which most formula is based on, however, contains a negligible oligosaccharide component. Additionally, bovine milk oligosaccharides lack the structural complexity and diversity of HMOs. So formula-fed infants do not obtain comparable oligosaccharide-fostered protections to those who are breastfed.

A case study: Group B strep

Based on these known effects of human milk oligosaccharides, my research group took an interest in Group B streptococcus. All mothers-to-be are screened during the third trimester of pregnancy for Group B strep; although it isn’t much threat to a healthy adult, this bacteria can be passed to the baby during labor and birth, with an increased risk of infection.

We noted that, even though Group B strep bacteria are present in breast milk, children who breastfeed are not at increased risk for Group B strep infection. Why? Could HMOs be providing protection against this bacteria?

To investigate, our team worked to isolate the complex sugars contained in donated human milk. With these molecules in hand, we began to test whether HMOs acted as antibiotics against Group B strep. In an initial study, we tried to grow Group B strep both in the presence and absence of HMOs. It turned out that HMOs do prevent the growth of Group B strep bacteria.

We also observed that different women produced HMOs with varying levels of antibiotic activity. This was not surprising as there are over 200 different HMOs in breast milk. Every woman produces a different set of sugars and they change during lactation. In followup studies, we showed that HMOs have antibiotic properties against a number of additional pathogens, including staph.

Going forward, our goals are to figure out exactly how these sugars are working and why specific women produce sugars that are more antimicrobial than others. Once researchers understand more about which HMOs are the most important ingredients in breast milk for baby health, these compounds can be synthesized and added to infant food products. A better quality infant formula that more closely mimics human breast milk may help close the health gap between breastfed and formula-fed babies.

Can you cut your cancer risk by eating organic?

Research Check: can you cut your cancer risk by eating organic?

The science isn’t clear on whether organic foods can lower your risk of cancer. But eating plenty of fruit and veg – however it’s grown – can reduce your risk.

A new study out this week has shoppers wondering whether it’s worth paying more for pesticide-free organic food.

The research, published in JAMA Internal Medicine, found those who chose more organically grown foods over 4.5 years had slightly lower rates of cancer, and in particular, lymphoma and postmenopausal breast cancer.

But while there is a correlation between eating organic foods and lower rates of cancer, it doesn’t necessarily mean one caused the other. People who choose organic foods are likely to be healthier, wealthier and better educated, all factors known to impact risk of cancer.

Read more: Clearing up confusion between correlation and causation

As the researchers note, this is the first study of its kind. The findings need to be confirmed in other studies before organic food can be proposed as a preventive strategy against cancer.

Past research has found, however, that higher intakes of fruit, vegetables and wholegrains – however they’re grown – and lower intakes of processed and red meats can decrease your risk of cancer.

So, if you don’t want to buy organic produce or can’t afford it, it’s fine to buy conventionally grown plant foods, especially if this means you eat more fruit and veg.

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How was the research conducted?

This research was part of the French NutriNet-Santé study and included almost 70,000 volunteers who were free of cancer.

At the beginning of the study, each participants’ diet was assessed based on the French nutritional guidelines and their food and drink consumption recorded in three 24-hour snapshots over two weeks.

Two months into the study, the participants were asked to provide specific information about their consumption of 16 categories of organically labelled foods. This included fruits, vegetables, soy-based products, dairy products, meat and fish, and so on.

The study included nearly 70,000 volunteer participants. Alyson McPhee

The participants were then given an “organic food score”. If they chose organically produced foods in all 16 categories, they would get a maximum score of 32.

The health of each participant was assessed each year and monitored for a median period of 4.5 years. When any cases of cancer occurred, details were independently confirmed with the individual’s hospital or treating physician.

What did they find?

The participants’ organic food scores ranged from 0.7 to 19.4. These were used to divide the group into equal quartiles.

The overall cancer risk was 25% lower in those who had the highest organic food score.

Cancers showing the greatest correlation with decreased risk were breast cancer (especially in postmenopausal women) and lymphomas (especially non-Hodgkin’s lymphoma).No correlation appeared with prostate or colorectal cancers, although the relatively short time frame would have made any change unlikely.

What do we need to take into account?

As previous studies with this group had shown, people who choose organically grown products tend to have higher income, higher levels of education and healthier diets. So the researchers adjusted for these factors.

They also made adjustments for other factors that could affect the outcome: age, sex, the month the participants were included in the program, marital status, physical activity, smoking status, alcohol intake, family history of cancer, body mass index, height, energy intake, and the intake of dietary fibre and also red and processed meat.

For women (who made up 78% of the study group), they also adjusted for the number of children they had, oral contraception use, postmenopausal status and use of hormonal treatment for menopause.

But although the researchers tried to adjust their results for these confounding factors, when so many are relevant in those who consumed more organically grown products, it’s hard to be definite about the validity of the findings.

Consumers of organic food tend to have healthier diets. Henrique Félix

Participants with a high organic food score also had generally healthier diets with higher intake of fruits and vegetables and lower consumption of red and processed meats. They also had lower levels of obesity.

So was it pesticides in conventional products that are related to some cancers, as the researchers hypothesised? Or is it that those who choose organic products over conventional foods have better diets and healthier lifestyles?

This research doesn’t, and can’t, tell us the answer.

This is the first study of its kind. The only study with some resemblance was a 2014 British study that asked women if they ate organic foods “never, sometimes, usually or always”.The British researchers found 21% less non-Hodgkin’s lymphoma in women who “usually or always” ate organic food. It also noted organic food eaters had a very slight increase in breast cancer (but the participants also drank more alcohol and had fewer children – both factors that can increase the risk of breast cancer).

In 2015, the International Agency for Research on Cancer classified some pesticides as “probably carcinogenic to humans”. This means there is limited evidence of a link between pesticide use and cancer in humans, but sufficient evidence of a link between pesticide use and cancer in experimental animal studies.

There’s also evidence that people who consume more organically grown products have lower levels of pesticide residue in their urine and some research showing that self-reported intake of organic produce can be used to predict urinary levels of metabolites of some pesticides. So it’s an area worthy of more research.The French study may have told us more if it included more accurate measurements of the various organically grown foods that were consumed and also the levels of particular pesticide residues in the participants’ urine.

An ideal way to study this issue in future would be to monitor rates of cancer in a group of similar people. Half would be given set amounts of organically grown foods; the other half would have the same amount of the same foods grown using conventional agriculture.

Their urinary levels of pesticide residues and the incidence of cancer over some years could then be assessed more accurately.

But the time and costs to conduct such a study make it unlikely to happen. – Rosemary Stanton

Blind peer review

The article is presents a fair, balanced and accurate assessment of the research study. – Tim Crowe

Read more: Research Check: will eating ‘ultra-processed’ foods give you cancer?

HRT and Breast Cancer.

There are not many topics in clinical medicine more polarizing than hormone replacement therapy (HRT) for women suffering from menopausal symptoms. Recently, The Lancetpublished a study finding “definite” excess risks of breast cancer associated with the use of HRT (with the exception of vaginal estrogen), and the issue included an accompanying editorial entitled “Menopausal hormones: definitive evidence for breast cancer.” 

It came as a welcome counterpoint when Carol Tavris and  Avrum Bluming sent me their response to the study, above. If you listened to my podcast with Avrum and Carol, and/or read their book on this very topic, Estrogen Matters, you have more context to appreciate Avrum and Carol’s response to the study provided in full, below.

– Peter Attia.   Much Ado About Little
Response to the recent Lancet paper on hormone therapy and breast cancer risk
Avrum Bluming, MD, and Carol Tavris, PhD

Here we go again, another round of scary headlines designed not to guide women through an informed decision process about Hormone Replacement Therapy (HRT)—also called Menopausal Hormone Therapy (MHT)—but to frighten them away from even considering it.(1)

And once again, a close reading of the study reveals that the data do not support the alarm.

Valerie Beral, the Head of the Cancer Epidemiology Unit at Oxford and the senior author of the paper, together with her widely respected colleagues, seem to enjoy working with large numbers, especially if the large numbers can identify a frightening, headline-worthy result.

As for this latest paper, here is a summary of our objections: 

The investigators reported having analyzed the data records of 108,647 postmenopausal breast cancer patients collected from dozens of previously published reports as well as unpublished data sets, and compared each patient with up to four randomly selected matched controls without a breast cancer diagnosis. In the accompanying editorial, Joanne Katsopoulos of the Women’s College Research Institute in Toronto, writes: “The complexity of the study design makes it difficult to appraise the results and most of us will take the results on face value.”(2) Read that statement again. When researchers dazzle readers with an avalanche of findings that require other professionals to “take the results on face value,” something is very wrong. It is the researchers’ job to make their data available—and readable—so that the data can be assessed independently. And yet Katsopoulos, while admitting it was “difficult to appraise the results,” apparently had no qualms titling her editorial “definitive evidence for breast cancer.” Definitive?

Even if their unclear assumptions are true and their difficult-to-understand calculations accurate, the Collaborative Group’s authors conclude that MHT administration would result in only one additional breast cancer for every 50 women who took it for 5 years, while taking estrogen alone would result in one additional breast cancer for every 200 women treated. We don’t intend to minimize the risks and fears associated with a diagnosis of breast cancer, but, as we show in Estrogen Matters, these absolute numbers indicate how non-frightening the results are, since these modest increases in absolute numbers are found in countless other medical studies of medications and treatments without generating panic about stopping them. 

Moreover, the authors fail to say that even if their finding of a small increased risk is valid,  breast cancer is currently curable in approximately 90% of newly diagnosed patients. Additionally, they fail to provide a balanced discussion of MHT’s benefits, which include relief from incapacitating menopausal symptoms, and reductions in the risks of cardiovascular disease (responsible for killing seven times more women than breast cancer), osteoporotic hip fracture, and Alzheimer’s Disease. 

We regret that Lancet is facilitating a wide dissemination of this unbalanced and inaccurate reporting. This paper does not provide meaningful guidance to clinicians, and it sows confusion and fear among patients.
Postscript: Some criticisms of the Million Women Study: A previous big-number study by Valerie Beral and associates.

The Million Women Study consisted only of 2 questionnaires separated by about 3 years and sent to over a million women. In spite of the grandiose title, only 44% of the sample responded to both surveys. A summary of the negative critiques of that paper summarized below is taken from several critical analyses (3,4,5):

  • The total incidence of breast cancer in this study, among all the women surveyed, was 1.4%. The investigators estimated that for every 1,000 women taking combination estrogen/progestin for 5 years, there would be an extra 6 cases of diagnosed breast cancer, and for every 1,000 women taking estrogen alone for five years, there would be an extra 1.5 cases.
  • Of that 1.4%, the increased risk of breast cancer was identified only in current hormone users but not in past users— even if past use had exceeded 15 years. The authors never explain or offer a biologic rationale for why current use is harmful and past use is not. This criticism has been leveled as well against The Collaborative Reanalysis,(6) The Nurses Health Study,(7) and the WHI.(8)
  • The average time from beginning therapy to diagnosis of breast cancer was brief (1.2 years), suggesting to clinicians that, in many cases, breast cancer had been present, but unidentified, before the women entered the study; the women who filled out the original questionnaire may have been aware of a problem in the breast, prompting their participation. The study appears to have been selecting this population with, not surprisingly, a high incidence of breast cancer. Perhaps, also not surprisingly, the median time from diagnosis to death from breast cancer in that study was only 1.7 years.
  • In a paper published eight years after the original Million Women Study report, the same investigators reported that the admittedly small increased risk of breast cancer seen among women taking estrogen was found only among those who started it within five years of reaching menopause. For those starting it more than five years after a final period, the incidence of breast cancer was the same as that found among never users.(9) How is this biologically plausible? The authors’ reliance on questionably generated numbers to the exclusion of biologic plausibility raises serious questions about the reliability of the conclusions they present. 

In 2012, Nick Panay, Chair of the British Menopause Society, wrote the following about the Million Women Study:

“I believe the use of statistics in this study is intimidating to most readers, and possibly to editors as well. I can’t help but feel that these authors decide what conclusions they want to publish, and use their data to construct the desired conclusion.”(10)

We could not agree more. 

Avrum Bluming, MD, and Carol Tavris, PhD


1. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy in breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet

 2. Kotsopoulos J. Menopausal hormones: definitive evidence for breast cancer. Lancet 2019;

3. Speroff L. The Million Women Study and breast cancer. Maturitas 2003;46:1-6.

4. van der Mooren MJ, Kenemans P. The Million Women Study: a licence to kill other investigations? Europ J Obstet Gynecol Reprod Biol 2004;113:3-5.

5. Shapiro S, Farmer RDT, Stevenson JC, et al. Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. Part 4. The Million Women Study. J Fam Plann Reprod Health Care. 2012;38:102-9.

6. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350:1047-59.

7. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med  1995; 332:1589-93.

8. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA  2002; 288: 321-33.

9. Beral V, Reeves G, Bull D, et al. for the Million Women Study Collaborators. Breast Cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 2011;103:296-305.

10. Panay N. Commentary regarding recent Million Women Study critique and subsequent publicity. Menopause International 2012; 18:33-5.

What to eat—and not eat—when you’re sick

What to eat—and not eat—when you’re sick

Liz Meszaros, MDLinx | September 16, 2019

The beautiful changing leaves and falling temperatures may herald the beginning of fall, but they also herald the beginning of conditions that viruses love. Colds and other illnesses are more prevalent during the fall and winter months because viruses thrive when temperatures range from 50° F to 30° F. And the flu virus has a special predilection for cold and dry weather, when it replicates and spreads most effectively.


The amino acid cysteine–as well as antinflammatory capabilities–may be what make chicken soup the quintessential feel-better food.

With this in mind, it’s best to be prepared. Here are some of the best foods to eat when you’re sick:

Chicken soup. Soups that are broth-based, including—and especially—chicken soup, are traditional fare for those who are ill. In fact, as long ago as the 12th century, physicians were recommending chicken soup for those who were ill. Since then, researchers have shown that the cornerstones of chicken soup’s benefits are its soothing and anti-inflammatory properties.

The secret ingredient in chicken soup may be cysteine, an amino acid found in chicken that helps thin mucus in the lungs. Couple this with the hot, steamy broth that helps moisten nasal passages, prevent dehydration, and fight inflammation—especially in the throat—and it’s no wonder that chicken soup has been a go-to for people who are sick for literally centuries.

In addition, researchers have shown that chicken soup significantly inhibits neutrophil migration to sites of infection or inflammation in patients with symptomatic upper respiratory tract infection. They also discovered that all of the ingredients in a traditional chicken soup (think vegetables, chicken, broth, etc)—individually exhibited this inhibitory capability.

Citrus fruits. Vitamin C may reduce the length and/or severity of colds, according to some studies. Eating citrus fruits that are high in vitamin C, therefore, is probably a good idea. Plus, the flavonoids found in oranges, lemons, grapefruits, and limes may give the immune system a boost, reduce inflammation, and help speed your recovery.

Popsicles. Although it seems counterintuitive, popsicles are a great choice when you are ill, and especially when your kids are ill. Proper hydration during illnesses, especially colds and respiratory infections, can help your body thin mucus and reduce congestion. In addition to being delicious, these icy treats can help soothe a sore throat. The healthiest choices include popsicles that are made of 100% whole fruit or those you’ve made at home with whole fruits. This way, you stay hydrated and get extra vitamin C and flavonoids to boot.

Garlic. This small member of the lily family—like onions, shallots, and leeks—is perhaps one of the most important ingredients in culinary preparation. Garlic has been used as a medicinal herb for centuries, and boasts a trifecta of therapeutic action: antibacterial, antiviral, and anti-fungal. It has also been shown to stimulate the immune system. In one study, researchers have found that taking garlic reduced the number of sick days by about 70% compared with not taking it.

Furthermore, people who took a garlic supplement were also sick less often than those who didn’t, and recovered a mean of 3.5 days faster, according to the results of another study. Finally, supplements of aged garlic extract were shown to not only enhance immune function, but decrease the severity of colds and the flu. Add garlic to chicken soup or a broth when you’re sick, and you will reap two-fold the benefits.

Bananas. Mild and sweet in flavor, bananas are easy to incorporate into your diet when you are sick, and especially helpful for gastrointestinal illnesses like norovirus. They contain many nutrients and several antioxidants, as well as soluble fiber, which can help relieve diarrhea. With very little protein and almost no fat, bananas provide 9% of the recommended daily allowance (RDA) of potassium, 33% RDA of vitamin B6, 11% RDA of vitamin C, and 14% RDA of manganese.

And on the flip side, here are some of the worst foods to eat when you’re sick:

Fatty foods. Because foods that are high in fat—like burgers and fries—are more difficult to digest than carbohydrates. Avoid them when you’re ill, especially if it’s with norovirus.

Dairy. For years, dairy foods were believed to promote mucus production; however, researchers have now found that this may simply be due to a placebo effect. Nevertheless, dairy foods—especially milk—can cause us to feel like we have thicker mucus. Just to be on the safe side, skip the milk and dairy products.

Sweets. Sugar has been implicated in suppressing the immune system and causing inflammation. Skip foods that are high in sugar—like doughnuts, pastries, and even many cereals—while you are convalescing with any illness.

Finally, the jury seems to be out on whether we should eat spicy foods when we are ill. Some camps claim that spicy foods are natural decongestants. Spicy offerings like wasabi, horseradish, or jalapeno peppers could help relieve congestion—a claim backed by several clinical trials. But, spicy foods are also notoriously hard on the stomach and can cause pain and gastrointestinal discomfort—the last things you need when you are already sick. And, if it’s norovirus that has you in its clutches, absolutely skip the spicy foods.

These common drugs may increase dementia risk

Top News in Internal Medicine

I am going to be in South Africa for the next 2 weeks, attending the 50th reunion of my medical school graduation class. I will be giving the Keynote address at the Alumni Symposium on how I helped prevent an environmental disaster in the 1980s. Dr Anne Nixon and Dr Mahdu will be looking after my patients in my absence.

These common drugs may increase dementia risk

Healthline/Medical News Today | June 25, 2019

A common class of drugs that doctors prescribe for a number of conditions—from bladder problems to Parkinson’s disease and depression—may increase a person’s risk of dementia, a large new study concludes.

New research by scientists from the University of Nottingham in the United Kingdom has analyzed the link between a certain class of drugs and the risk of dementia. The drugs in question, called anticholinergics, work by inhibiting a chemical messenger called acetylcholine.

Their effect is to help relax or contract muscles, and doctors can prescribe them to help treat bladder conditions, gastrointestinal problems, and some of the symptoms of Parkinson’s disease.

In their new study, which looked at data from tens of thousands of participants, the researchers concluded that anticholinergics may increase a person’s risk of developing dementia. The National Institute for Health Research funded this study, and the scientists published their findings yesterday in JAMA Internal Medicine.

An almost 50% increase in risk

For their study, lead researcher professor Carol Coupland and team analyzed the medical records of 58,769 people with dementia and 225,574 people without dementia. They were all 55 years old or above at baseline.

Among those with dementia, 63% were women and the average age was 82. For each person with dementia, the researchers found five control matches of the same age and sex and who attended the same general practice to receive medical care.

Coupland and colleagues sourced the data from the QResearch database and looked at medical records from between January 1, 2004 and January 31, 2016.

The researchers found that anticholinergic drugs in general were associated with a higher risk of dementia. More specifically, however, anticholinergic antidepressants, antipsychotic drugs, anti-Parkinson’s drugs, bladder drugs, and epilepsy drugs were associated with the highest increase in risk.

Among these, the most frequently prescribed drugs were antidepressants, anti-vertigo drugs, and bladder antimuscarinic drugs (for the treatment of overactive bladder).

These results remained even after the researchers controlled for confounding variables (or known risk factors for dementia), including body mass index (BMI), smoking status, alcohol use, cardiovascular problems, and the use of other medication, such as antihypertensive drugs.

All in all, the researchers concluded that people aged 55 or over who had taken strong anticholinergics on a daily basis for at least 3 years had an almost 50% higher chance of developing dementia than people who had not used this type of medication.

“This study provides further evidence that doctors should be careful when prescribing certain drugs that have anticholinergic properties,” explains study co-author professor Tom Dening.

“However,” he warns, “it’s important that [people] taking medications of this kind don’t just stop them abruptly, as this may be much more harmful. If [people] have concerns, then they should discuss them with their doctor to consider the pros and cons of the treatment they are receiving.”

‘Risks should be carefully considered’

To assess the strength of anticholinergic drugs and how often the participants took them, the team looked at available information about prescriptions over a period of 10 years. However, they note that this is an observational study, so they cannot confirm whether the drugs are directly responsible for the increased risk of dementia. The researchers add that doctors may have prescribed some of these drugs to their patients precisely for the treatment of very early dementia symptoms.

Nevertheless, Coupland argues that the “study adds further evidence of the potential risks associated with strong anticholinergic drugs, particularly antidepressants, bladder antimuscarinic drugs, anti-Parkinson’s drugs, and epilepsy drugs.”

“The risks of this type of medication should be carefully considered by health-care professionals alongside the benefits when the drugs are prescribed and alternative treatments should be considered where possible.”

—Professor Carol Coupland

“These findings also highlight the importance of carrying out regular medication reviews. We found a greater risk for people diagnosed with dementia before the age of 80, which indicates that anticholinergic drugs should be prescribed with caution in middle-aged people as well as in older people,” she concludes.

Sexual hormone oestradiol protects female brain in mid-life

We constantly hear the negative side of oestrogen in women, and rarely the positive side. This will interest most of you.

Sexual hormone oestradiol protects female brain in mid-life

Recent research suggests that increased visceral fat – that is body fat surrounding a number of important internal organs such as the liver, pancreas and intestines – carries the risk of cognitive impairment in later life. “Our goal was to investigate whether excess organ fat is associated with a reduction in the structural networks and storage capacity of our brain throughout its lifetime. We also wanted to find out whether this interaction can be influenced by oestradiol,” said Rachel Zsido.

Oestradiol is a hormone consisting of cholesterol and is the strongest of the three naturally produced oestrogens. It is the most important hormone found in the female body and has many amazing functions – it contributes decisively to the maintenance of the female reproductive system. Men also produce oestradiol, but in much smaller amounts. In both sexes, oestradiol is also produced by fatty tissue, the brain and the walls of blood vessels. It also has a vasodilative and antioxidant effect. Oestradiol can help maintain myelin architecture – and thus the membrane that protects our nerves.

Although visceral fat and estradiol appear to play opposite roles in the healthy ageing process of the brain, it remains unclear how and at what point they interfere with brain structure. To solve this mystery, Zsido and her colleagues examined a large data set of healthy adults aged between 20 and 80, 501 men and 473 women, from the LIFE study. “We looked at the brain structure and body fat of the volunteers on images taken from the magnetic resonance tomograph, as well as their memory and oestradiol levels in the blood. Our results suggest that increased organ fat expands the negative influence of aging on brain networks in men and women. We have also found that men prepare this organ fat earlier, while women are particularly affected in mid-life,” the scientist explains.

“The decrease in oestradiol in this middle phase of life accelerates the normal aging process. It seems, however, that oestradiol protects women’s brains from structural damage to the gray matter during the middle of life”, adds Julia Sacher, who along with her research group is investigating the effects of hormonal changes on mood, emotional well-being and cognition. “We took a closer look at a subgroup of women between the ages of 35 and 55 and found that a low level of oestradiol is associated with weaker memory performance in the middle of life. This is also the age range in which the transition to menopause occurs, which is initially characterised by abrupt oestradiol fluctuations and finally by a stop in the reproductive phase. We therefore believe that the pre-menopausal phase provides an important window of opportunity to prevent accelerated brain aging and the development of neurodegenerative diseases such as dementia or depression in women.

Hormones important in risk recognition for dementia or depression

A second joint study led by Julia Sacher and Steffi Riedel-Heller from the Institute for Social Medicine, Occupational Medicine and Public Health (ISAP) also showed a decisive interaction between unfavourable metabolic states and another important sex hormone, testosterone. The team found that elevated testosterone levels and changes in body weight have different effects on women’s susceptibility to depression before and after menopause. “Together, the results from both studies emphasize the need to further consider sex differences and sex hormones when investigating the risk of neurodegenerative diseases,” summarizes Julia Sacher. This is particularly important in mid-life, as this transitional phase offers women a special opportunity for prevention.



Changes in estradiol during aging are associated with increased dementia risk. It remains unclear how estradiol supports cognitive health and whether risk factors, such as midlife obesity, are exacerbated by estrogen loss.


To assess whether visceral adipose tissue (VAT) moderates the association between age and brain network structure and to investigate whether estradiol moderates the association between VAT and brain network structure.

Design, setting, and participants:

Cross-sectional study of data from 974 cognitively healthy adults in Germany who participated in the Health Study of the Leipzig Research Centre for Civilization Diseases, a previously described population-based cohort study. Two moderation analyses were performed, including VAT as the moderator variable between age and brain network structure and estradiol as the moderator variable between VAT and brain network structure. The study was conducted from August 1, 2011, to November 23, 2014. Analyses were conducted from August 2017 to September 2018.


Serum estradiol levels from fasting blood and visceral adipose tissue volume from T1-weighted magnetic resonance imaging (MRI).

Main outcomes and measures:

Brain network covariance (individual loading on structural network derived from T1-weighted MRI) and memory performance (composite score from the Consortium to Establish a Registry for Alzheimer Disease [CERAD] verbal episodic memory test on learning [score range, 0-30], recall [score range, 0-10], and recognition [score range, 0-20]).


Final analyses included data from 473 women (mean [SD] age, 50.10 [15.63] years) and 501 men (mean [SD] age, 51.24 [15.67] years). Visceral adipose tissue was associated with an exacerbation of the negative association of aging with network covariance for women (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P = .001) and men (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P < .001). Estradiol level was associated with a reduction in the negative association of VAT with network covariance in women (interaction term β = 0.63; 95% bias-corrected bootstrap CI, 0.14-1.12; P = .01), with no significant association in men. In the female midlife subgroup (age range, 35-55 years, when menopause transition occurs), low estradiol levels were associated with lower memory network covariance (Cohen d = 0.61; t80 = 2.76; P = .007) and worse memory performance (Cohen d = 0.63; t76 = 2.76; P = .007).

Conclusions and relevance:

This study reports a novel association between VAT, estradiol, and structural brain networks as a potential mechanism underlying cognitive decline in women. These findings appear to highlight the need for sex-specific strategies, including VAT and hormonal screening during midlife, to support healthy cognitive aging.


Zsido RG, Heinrich M, Slavich GM, Beyer F, Kharabian Masouleh S, Kratzsch J, Raschpichler M, Mueller K, Scharrer U, Löffler M, Schroeter ML, Stumvoll M, Villringer A, Witte AV, Sacher J.  Association of Estradiol and Visceral Fat With Structural Brain Networks and Memory Performance in Adults. JAMA Netw Open. 2019 Jun 5;2(6):e196126. doi: 10.1001/jamanetworkopen.2019.6126.

More on Oestrogen and Breast Cancer

Breast Cancer (Auckl). 2019 May 15;13:1178223419844198. doi: 10.1177/1178223419844198. eCollection 2019.

The word apoptosis means: Apoptosis removes cells during development. It also eliminates pre-cancerous and virus-infected cells, although “successful” cancer cells manage to escape apoptosis so they can continue dividing. Apoptosis maintains the balance of cells in the human body and is particularly important in the immune system.

Pro-Apoptotic Effects of Estetrol on Long-Term Estrogen-Deprived Breast Cancer Cells and at Low Doses on Hormone-Sensitive Cells.

Yue W1, Verhoeven C2, Bernnink HC2, Wang JP1, Santen RJ1.

Author information

1Department of Medicine, Division of Endocrinology & Metabolism, University of Virginia Health Systems, Charlottesville, VA, USA.2Pantarhei Oncology, Zeist, The Netherlands.



Postmenopausal women with estrogen receptor-positive breast cancers often respond initially to tamoxifen or aromatase inhibitor therapy. Resistance to these treatments usually develops within 12 to 18 months. Clinical studies have demonstrated that high-dose estrogen can induce regression of these endocrine-resistant tumors. However, side-effects of high-dose estradiol (E2) or diethylstilbestrol (DES) limit their usage. Estetrol (E4) is the most abundant estrogen during pregnancy and has a long half-life and a low potential for side-effects. Estetrol might then provide benefits similar to DES on tumor regression but with lesser toxicity.


In this study, we systematically evaluated the effects of E4 on cell proliferation and apoptosis in wild-type MCF-7 and long-term estrogen-deprived (LTED) MCF-7 cells and compared its effects with E2 and estriol (E3).


Estetrol induced apoptosis in LTED cells but stimulated growth of MCF-7 cells at concentrations from 10-11 to 10-8 M. These effects of E4 are similar to those of E2 but require much higher doses. Differing from E2, E4 at 10-12 M induced apoptosis in MCF-7 cells and another pregnancy estrogen, E3, acted similarly. No antagonistic effect of E4 or E3 against E2 occurred when they were combined.


The pro-apoptotic effects of E4 and E3 on LTED cells and at low doses on MCF-7 cells indicate that these steroids could be used as therapeutic agents for endocrine-resistant or sensitive breast cancer.

J Endocrinol. 2015 Jan;224(1):85-95. doi: 10.1530/JOE-14-0549. Epub 2014 Oct 30.

Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.

Gérard C1, Blacher S1, Communal L1, Courtin A1, Tskitishvili E1, Mestdagt M1, Munaut C1, Noel A1, Gompel A2, Péqueux C3, Foidart JM1.

Author information

1Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.2Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France.3Laboratory of Tumor and Development BiologyGIGA-Cancer, Institute of Pathology, University of Liège, CHU-B23, B-4000 Liège, BelgiumINSERM-UMRS 938Université Pierre et Marie Curie (UPMC), F-75005 Paris, FranceGynaecological Endocrinology UnitParis Descartes University, Hôpitaux Universitaires, F-75006 Paris, France


Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E2), E4 has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared with E2, E4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E4 was 100 times less potent than E2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERα (ESR1) is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties toward the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation

Oncotarget. 2015 Jul 10;6(19):17621-36.

Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms.

Gérard C1, Mestdagt M1, Tskitishvili E1, Communal L2, Gompel A2,3, Silva E4, Arnal JF5, Lenfant F5, Noel A1, Foidart JM1, Péqueux C1.

Author information

1Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium.2Gynaecological Endocrinology Unit, Paris Descartes University, Hôpitaux Universitaires, Paris, France.3INSERM U938, Université Pierre et Marie Curie, Paris.4Institute of Environment, Health and Societies, Brunel University London, Uxbridge, United Kingdom.5INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, University of Toulouse, UPS, Toulouse, France.


Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERα) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms.