When it comes to balancing hormonal changes during the transition to menopause, less can be more. Researchers at the University of São Paulo (USP) in Brazil demonstrated this when testing an alternative strategy to conventional therapy. Rather than replacing estrogen entirely, the team activated only one type of estrogen receptor in the cells. This approach achieved a broad and beneficial metabolic effect without stimulating the growth of reproductive tissues, such as the uterus and breasts. This is important for individuals with a genetic predisposition to developing tumors.
"It's a more targeted strategy. By acting only on that receptor, we were able to rebalance the metabolic effects of the drop in estrogen during menopause without affecting potentially sensitive areas of the body," explains the researcher Débora Santos Rocha , a FAPESP postdoctoral fellow at the Institute of Chemistry (IQ-USP) and first author of the article published in the journal Comprehensive Physiology.
The study was conducted on female rats that had their ovaries removed to simulate menopause. In this model, the researchers used an experimental drug to activate only estrogen receptor beta (ERβ), which is an important regulator of metabolism and does not stimulate reproductive tissues or increase the risk of hormone-sensitive tumors.
As Rocha explains, the significant drop in estrogen during the transition to menopause disrupts the entire metabolism, potentially promoting the accumulation of visceral fat, insulin resistance, and cardiovascular risk. "In addition to their importance in reproduction, estrogens play a central role in energy regulation. When their levels decrease, widespread metabolic changes also occur, increasing the risk of metabolic syndrome and diseases such as diabetes and hypercholesterolemia [high cholesterol]," she states.
Conventional hormone replacement therapy attempts to counteract this loss by providing estrogen and progesterone through pills, patches, or creams. However, by activating all estrogen receptors indiscriminately, it may increase the risk of tumor growth in predisposed women. "It isn't hormone replacement therapy that causes cancer. What happens is that if there are tumor cells in estrogen-sensitive tissues, such as the uterus, breast, or endometrium, they may respond to the hormone and multiply more quickly," Rocha explains.
A targeted solution with broad benefits
The results of the study show that the isolated activation of ERβ promoted profound metabolic reprogramming. "With the new approach, we restored fasting blood glucose levels, normalized the lipid profile, and reduced the size of fat cells. The pancreatic islets [cells that produce insulin and other hormones] regained their normal shape, and blood levels of cholesterol, triglycerides, and free fatty acids returned to healthy levels. All of that occurred without any effect on the uterus, which indicates the safety of the approach," comments Alicia Kowaltowski , a professor at IQ-USP and the research coordinator.
The study primarily focused on the liver. This is because the organ begins to process fats differently during the transition to menopause and in the absence of estrogen. "Lipid metabolism changes significantly, and the liver accumulates more fat. 'Bad' cholesterol [LDL] in the blood increases, and various lipid profiles are altered. However, with the activation of ERβ, those parameters returned to normal," says Rocha.
The same effect was observed in the analysis of isolated liver cells. "The drug remodels the metabolism of liver cells [hepatocytes], causing them to oxidize fatty acids more [i.e., to 'burn' the building blocks of lipids to generate energy]. That reduces fat accumulation and improves the overall lipid profile. By activating that specific pathway, we modulate liver metabolism and make circulating lipids healthier," the postdoctoral fellow explains.
Kowaltowski highlights another important finding from the study. "By activating ERβ, the drug causes liver cells to fully oxidize fatty acids, something that normally doesn't happen since the liver typically performs only partial oxidation, generating ketone bodies [alternative energy sources that the body creates to compensate for a lack of carbohydrates]. With that 'complete oxidation,' fat is fully converted into CO₂, significantly improving the body's lipid profile. It's important to note that this pathway can be activated to provide metabolic benefits – something we hadn't imagined," she explains.
There is no one-size-fits-all model
Although the treatment did not prevent the weight gain characteristic of menopause, the authors note in the article that it broadly improved metabolic quality and the functioning of the liver, pancreas, and blood.
"Menopause is a phase characterized by a wide variability of symptoms among women, which makes it important to have a variety of therapeutic approaches. If we can modulate specific pathways, we pave the way for more personalized treatments. Perhaps the approach we're presenting won't be ideal for one person, but it could be decisive for another. The important thing is to have treatment options," Kowaltowski emphasizes.
The research continues in a new project funded by FAPESP that is now focused on the transition to menopause (perimenopause), using an experimental model that more closely mimics human reality.
Rather than abruptly removing the ovaries from female rats, the new study will use a model of gradual ovarian reserve decline, enabling the researchers to observe hormonal change dynamics throughout the process. "We want to understand that transition and identify new therapeutic targets that could serve as alternatives to conventional hormone replacement therapy," Rocha concludes.
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
