Hormonal fluctuations affect women’s immunity, but a lack of rigor in studies still prevents a consensus

Researchers at São Paulo State University are investigating how hormonal fluctuations throughout a woman’s life influence the immune system and how physical exercise can mitigate these effects.

By Maria Fernanda Ziegler  |  Agência FAPESP – Hormonal fluctuations throughout a woman’s life are among the factors that most influence the immune system. Like a seesaw, variations in estrogen and progesterone affect cellular levels and alter the immune and inflammatory profiles. For example, inflammatory activity is most intense in the days leading up to the menstrual period (luteal phase). During menopause, a drop in sex hormones promotes a pro-inflammatory state.

Despite our understanding of the relationship between hormonal fluctuations and the immune system, scientists still disagree about the real impact of the menstrual cycle, perimenopause, and menopause on women’s immunity.  The reason for this lack of consensus is simple: inadequate characterization of the menstrual cycle in some studies on the subject.  

This was demonstrated in a review conducted by researchers at São Paulo State University (UNESP) in Presidente Prudente, Brazil, supported by FAPESP. The researchers found that many of the main studies published on the subject are still based on simplified methods, such as cell phone apps, to determine a woman’s current phase of her menstrual cycle.  

“According to the main international guideline, simplified methods only tell us whether the person is menstruating or not, and this is insufficient for scientific studies. A combination of methods must be used to identify whether she is in the follicular, ovulatory, or luteal phase, because in each of these stages, there are variations in progesterone and estrogen, hormones that have different implications for the immune system,” explains Barbara de Moura Antunes, the researcher who conducted the study.
 
Antunes explains that this methodological gap has produced conflicting results in research on the topic. “The inconsistency and difference in the methods used to control sex hormones means that we have diverse and, consequently, inconclusive results. And this doesn’t fill gaps in knowledge; it only generates more confusion and misinformation,” she says. 

According to the researcher, the lack of consensus and rigor in research stems from an earlier problem: the failure to include women in scientific studies. “For many years, it was recommended that clinical trials and animal studies be conducted only with men or male animals. However, the female body experiences constant hormonal fluctuations, unlike the male body, which maintains more stable levels throughout life. Ignoring this dynamic compromises our understanding of women's health,” she says.

The review study published in the journal Maturitas opens up a new line of research that aims to investigate this relationship and the impact of physical exercise in these different scenarios throughout a woman’s life in greater depth. 

The team responsible for the article is now preparing for the next stage: conducting an original study with Brazilian women that promises to address these gaps. “Does the level of physical activity or fitness associated with hormonal fluctuations impact the inflammatory response? Is there an ideal type of physical exercise for immunity? Should training variables be adjusted over time? How do these hormonal fluctuations impact sedentary, active, and trained women? We intend to investigate all of this in order to broaden our understanding of the health of half the population,” the researcher told Agência FAPESP. 

The research will be divided into two phases. The first will analyze women of reproductive age (18-35 years old) classified by cardiorespiratory fitness levels. The goal will be to investigate how the inflammatory response is modulated by different phases of the menstrual cycle. The second phase will include premenopausal, menopausal, and postmenopausal women also divided by fitness level to evaluate the impact of hormonal changes.

Antunes explains that, thus far, it is known that, during a woman’s reproductive life, levels of estradiol (a specific type of estrogen) and progesterone fluctuate throughout the menstrual cycle, directly influencing the immune system. These fluctuations affect immune cells, such as monocytes and lymphocytes, which have receptors for sex hormones. Consequently, they respond to this stimulus by producing cytokines, which are signaling proteins that regulate inflammation.

Antunes explains that from menstruation to ovulation (the end of the follicular phase), estrogen levels are high and progesterone levels are low. This favors an anti-inflammatory response and improves physical and cognitive performance. During the luteal phase, which precedes menstruation, estrogen levels drop while progesterone levels rise. This makes the body more susceptible to inflammation, fatigue, and delayed muscle recovery.

Studies conducted by the group show that during the follicular phase, anti-inflammatory and health-protective markers (such as IL-1ra and HDL-c) are more prevalent, while pro-inflammatory markers (such as TNF-α and IL-6) predominate during the luteal phase.

“With aging, especially during menopause, there’s a marked decline in estradiol, which is associated with several health problems, such as cardiovascular disease, loss of muscle mass [sarcopenia], osteoporosis, and changes in lipid metabolism,” she says.

The studies also showed that, although physical exercise does not reverse the decline in estradiol, it acts as a powerful tool to prevent and treat the negative effects of aging. “It improves the production of anti-inflammatory cytokines, strengthens muscles and bones, and helps maintain women’s overall health at all stages of life,” she says.

The article “Immunometabolic insights into women’s health across all ages” can be read at www.sciencedirect.com/science/article/abs/pii/S0378512225005274.