Menopause Raises the Risk of Fatty Liver Diseaseq

Bodily changes during the menopause transition increase the risk of metabolic conditions such as obesity and diabetes. They also sharply raise the odds of a related condition: nonalcoholic fatty liver disease, now called metabolic dysfunction-associated steatotic liver disease (MASLD).

It’s long been known that metabolic syndrome is the main cause of MASLD, but scientists are starting to wonder if menopause itself could lead to fatty liver disease.

“It’s very difficult to disentangle what is truly due to menopause, meaning low estrogen levels, versus what’s due to chronological aging. What is truly menopause, and what is due to other lifestyle factors?” said Monica Christmas, MDassociate medical director at the Menopause Society.

Teasing out that difference could help clinicians treat a condition that is becoming increasingly deadly for older women.

After age 50, around the time of menopause, women are 20% more likely to develop metabolic dysfunction-associated steatohepatitis (MASH), a severe form of MASLD, and progress to advanced fibrosis than men of the same age. MASH is becoming more common in postmenopausal women and is now the primary reason for liver transplantation in this group.

The research on the link between menopause and liver health is nascent. So far, only a smattering of animal studies and small observational studies have suggested a link. In bits and pieces, scientists are starting to peel back the effects of metabolic syndrome to see if estrogen depletion is causing fatty liver. If that proves to be true, it may open avenues for hormone therapy to support liver health through menopause.

Research into hormone therapy over the past few decades has focused on other health conditions, said Cynthia Stuenkel, MDa clinical professor of medicine at the University of California San Diego and an attending physician for the university’s Endocrinology and Metabolism Service.

Now, she said, interest in the effects on liver health is “bubbling up.”

“If you look at obesity maps, it’s kind of terrifying. That’s why people are saying, ‘Wait a minute, look at this, and then look at the timing—maybe there is a menopause effect,” Stuenkel said. “I think we’re going to be hearing a lot more about this.”

Parsing Menopause from Metabolic Changes

Many women experience the first symptoms of perimenopause in their late 30s to 40s. That’s when the balance of sex hormones starts to shift. Namely, estrogen dips, causing a cascade of changes to the skin, heart, vagina, and other organs. The median age for menopause—when a woman no longer gets her period—is 52.

During this period, the body tends to store fat differently. Where there used to be more surface-level fat, women may start accumulating it deeper in the abdomen. This visceral fat is strongly linked to insulin resistance, inflammation, and a higher risk of fat accumulation in the liver.

If a postmenopausal woman doesn’t experience overweight or metabolic syndrome, would her changing hormones still put her at greater risk for MASLD?

Several animal studies and early human trials have started to probe that question.

In one observational study, researchers found that postmenopausal women had a higher likelihood of developing severe liver fibrosis compared to younger women. However, that group included many women with obesity, which could have contributed to their outcomes.

When a different research group applied the same model to women with MASLD but without obesity, they found a 2.2-fold increase in severe fibrosis risk in the post-menopause group. The authors hypothesized that the risk difference has more to do with menopause than age.

Another study looked at women with endometrial cancer whose ovaries were removed as part of their treatment, accelerating their menopause. The women who were younger than 40, who likely hadn’t yet experienced natural menopause, had a significantly greater risk of developing MASLD after the procedure.

However, the authors noted that the outcome was also associated with diabetes and high cholesterol, showing the challenge of separating the effects of metabolism from menopause.

Studies like these aren’t robust enough to conclude that the menopause transition causes liver fat build-up, Stuenkel said. They are, at this point, “hypothesis-generating.”

They do suggest some possible mechanisms, however. For instance, scientists know that changes in estrogen could alter certain parts of the immune system and boost inflammation. Such immune shifts could leave the liver vulnerable to disease progression.

Stuenkel said it’s possible that testosterone and other hormones play a significant role in liver health, too.

“When I talk to people, I really like to be able to give a strong bottom line, one way or another. But I feel like it would be premature and just not accurate to take a really strong stand about what we should do with women in your practice right now,” Stuenkel said.

Estrogen as a ‘Protective Blanket’ for the Liver

It’s possible that estrogen is acting as a protective blanket for the liver. Once it depletes, the liver could be left vulnerable to fat build-up and scarring, explained Johanna Dystefano, PhDprofessor and head of the Metabolic Disease Research Unit at TGen, a genomics research institute in Arizona.

“I would imagine that this is a kind of dynamic process where, before menopause, the body has a number of ways to mitigate effects on the liver, but that changes following menopause,” she said.

The underlying question, she said, is whether menopause hastens the development of cirrhosis in women who already have fatty liver. To better understand that relationship, DiStefano said she’s studying genetic characteristics of normal-weight women who don’t have metabolic dysfunction.

“If someone who doesn’t have obesity goes through menopause, but they have a genetic susceptibility that, up until this point, had been mitigated by the presence of estrogen, that genetic predisposition could then manifest because the protection has been lost,” DiStefano said.

Hormone Therapy as a Potential MASLD Treatment

Perhaps the next step to understanding if menopause directly increases MASLD risk is to see if reversing its effects can help. If the dip in estrogen that occurs during menopause is responsible for making someone more susceptible to fatty liver disease, then restoring some of the lost estrogen would surely reduce that risk.

In a 2020 review paper, DiStefano highlighted several clinical studies showing that small groups of postmenopausal women who took hormone therapy had better liver health than those who didn’t. A review article published this year said, “Clinical studies are few, and their data are conflicting.”

While there’s no strong evidence yet that hormone therapy can help the liver, scientists know a bit about what harms it.

It’s common for providers to prescribe an estrogen pill for menopause management, but these oral formulations are processed in the liver, where they could be potentially damaging. The FDA labels for many oral hormone therapies list liver disease as a contraindication.

Some studies indicate that giving estrogen transdermally could lead to better outcomes for people with liver disease. That includes using a skin patch, gel, or vaginal ring that allows hormones to absorb through the skin and into the bloodstream, bypassing the liver.

A small study of postmenopausal women found that the rates of MASLD increased in the group that was given an oral menopause hormone therapy, but decreased among those who used a transdermal option.

Christmas said that if someone presented to their hepatologist with fatty liver, their provider wouldn’t put them on hormone therapy to treat that disease. But if they also had severe hot flashes, transdermal estrogen might provide some relief. If that estrogen replacement proves to help their liver health, that’s an added benefit.

For decades, Stuenkel has been involved with creating the clinical guidelines for hormone use for the Menopause Society and Endocrine Society. As far as she knows, those organizations haven’t featured the liver-menopause connection in their meetings or considered it a focal point in their research.

Researchers at Oxford have published their plans to perform an in-depth study this year. They plan to follow 10 women who are starting hormone therapy for the first time to understand how that treatment affects their liver fat and other metabolic outcomes. A study like this will provide a useful baseline to help inform clinical trials down the line, Stuenkel said.

Those studies will have to answer numerous questions: When is the best time to start giving MHT for liver health? How long can someone safely and effectively use it? What’s the right dose? Can it be used to prevent the disease, treat it, or both?

How to Manage Your Liver Health Through Menopause

The population of aging women in the U.S. is growing, and they’re living longer. Most women will spend a third or more of their lives in postmenopause.

“If there are specific medical comorbidities that are truly just related to menopause, and if managing the symptoms with hormone therapy or something else can help mitigate the progression of that disease process, it absolutely is imperative that we do that,” Christmas said.

It may be helpful to ask your internist to help you establish a health baseline when you’re early in perimenopause, DiStefano said. Checking your liver enzymes, cholesterol, and other metabolic measurements can give you a sense of where your health is starting. That way, you can better track the metabolic changes that occur during menopause and adjust your lifestyle accordingly.

She said you may have to request that information yourself or push for more clarity about the results of your liver enzyme tests. Given the newness of the research, it’s possible that your healthcare providers aren’t yet thinking about the risk of MASLD or MASH in your menopause care.

“Unfortunately, women really have to take responsibility for their health. It’s unrealistic to depend on their primary care provider or someone else to recommend blood work or other strategies,” DiStefano said. “Your doctor is only as good as her or his depth of knowledge in that area.”

For now, it’s well-established that certain lifestyle changes can drastically decrease a person’s risk of developing fatty liver or progressing from MASLD to MASH.

Numerous studies find that a Mediterranean-style diet can reduce the risk of metabolic syndrome and the health conditions associated with menopause. Getting adequate exercise, including resistance training, minimizes muscle loss in older years. Avoiding smoking, alcohol, and processed foods can all help keep your liver humming.

“We’re not going to get another body. We don’t get a trade-in. Even if we have medication that helps to manage things, it’s so much better if we can actively be doing things that keep us healthy, mentally and physically,” Christmas said.