Female Hormones Found to Dramatically Influence Body’s Internal Clock
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A groundbreaking new study reveals that female sex hormones, particularly progesterone, exert a significant influence on the human body’s circadian rhythms, potentially explaining variations in health and behavior linked to hormonal fluctuations. Researchers have developed an innovative method, called CircaSCOPE, to map these internal clocks across numerous cells, uncovering a complex interplay between hormones, cellular timing, and overall health.
Every human body possesses a central circadian clock in the brain responsible for regulating daily rhythms, but increasingly, scientists recognize that nearly every cell also contains its own internal clock. These cellular clocks, while influenced by the central brain clock, operate with a degree of independence, creating a network of synchronized timers throughout the body.
The research team utilized CircaSCOPE to demonstrate that female sex hormones – especially progesterone – alongside the stress hormone cortisol, have a dramatic effect on setting these internal timers. “We now know how these clocks communicate, so maybe we can explain their involvement in various disorders and pathologies, and help patients whose internal timing is disrupted,” a senior researcher stated.
Disruptions in circadian rhythm synchronization can lead to serious health issues, including sleep disorders, diabetes, and even cancer. The body “needs to synchronize millions of clocks because they are present in every cell in our body,” explained Prof. Gad Asher of the Weizmann Institute of Science’s Asher lab.
The study highlighted the particularly prominent effect of female hormones compared to their male counterparts. “Sex hormones are very important in shifting the clock,” Asher said. “Female hormones have a much more prominent effect compared to male hormones.” While the precise impact on men remains unclear, researchers acknowledge the need for further investigation. Currently, the experiments have been conducted in cell cultures and have not yet been validated in animal or human models.
The findings also offer potential insights into circadian disruptions experienced during menstruation, pregnancy, and menopause. The research could pave the way for targeted therapies to address these hormonal imbalances and their impact on internal timing.
The study, led by Dr. Gal Manella, Dr. Saar Ezagouri, and Nityanand Bolshette, was published in the scientific journal Nature Communications.
Beyond a Single Clock: The Cellular Network of Time
For years, the prevailing understanding was that a single master clock in the brain governed all physiological processes. However, approximately 25 years ago, scientists discovered the existence of clocks within every cell and tissue throughout the body. These circadian clocks are not solely influenced by external cues like sunlight but also by signals circulating through the bloodstream.
When the body’s internal time is misaligned with the external environment, a range of health problems can arise. “The best example is jet lag or shift workers, in which the person’s internal time is not in accordance with the environmental time,” Asher explained. The brain receives signals from the eyes regarding light and darkness, but emerging evidence suggests that illnesses may stem from a lack of synchronization between clocks in different organs. “The clock in the liver should be synchronized, or should show a similar time as the clock in the kidney or the clock in the brain, but this is not always the case.”
Oxygen’s Role and the CircaSCOPE Breakthrough
Researchers in Asher’s lab have also demonstrated that oxygen levels act as a crucial signal for internal clocks, helping them maintain accurate timekeeping. An expedition to La Rinconada, Peru – the highest permanent settlement in the world at 5,300 meters (17,388 feet) above sea level – revealed that lower oxygen levels altered the daily rhythm of many genes. These findings may be relevant to the increased incidence of low oxygen-related pathologies, such as heart disease and asthma exacerbation, during early morning hours.
Prior to the development of CircaSCOPE, mapping these blood-borne signals and their effects on cellular clocks proved challenging. The new method utilizes an array of human cells, each representing a different time of day, resembling a “wall of clocks” displaying the current time across various global locations.
Despite a minor delay caused by the Iranian ballistic missile strike in June 2025, which impacted the lab, researchers were able to monitor the clock in every cell and characterize how it responded to different signals. This innovative approach drastically reduces the time required for analysis, enabling the screening of dozens of compounds within a single week. “If we suspect that a certain compound affects the clock, we add it to the cells, and we can see exactly where their clocks are moving in each cell,” Asher said. “This is a very powerful approach which can generate a lot of information about how the clock is responsive to different signals.”
CRY2: A Key Protein in Hormonal Signaling
The study also identified the protein CRY2 (Cryptochrome 2) as the primary component receiving hormonal signals within the clock, challenging previous assumptions that PER2 (Period 2) played this role. “It seems that the sex hormones, as well as many other signals, are acting through the CRY2 protein,” Asher explained. “It probably transfers the information into the clock in the cell.”
Prof. Yoav Gothilf of Tel Aviv University, who was not involved in the study, noted the evolutionary significance of this finding. In early organisms, CRY2-like proteins functioned as light sensors. As animals evolved, CRY2 retained its role in synchronizing internal clocks, but the signal it responded to shifted from light to hormones in mammals. “It seems the role of CRY2 in synchronizing clocks has been conserved, but the signal it responds to has changed, from light in early life forms to hormones in mammals,” Gothilf said.
Gothilf added that the research suggests “daily, age-specific waves of hormones can shift the timing of our internal clocks,” offering a biological explanation for the shift from morning preference in childhood to night-owl tendencies during adolescence and back again in adulthood.
Asher’s lab plans to continue investigating the role of hormones in circadian clocks, potentially extending the research to animal models. “We can now identify compounds, and we identify that the sex hormones are important, changing throughout life,” he said. “Identifying molecules that are potent time signals for clocks has major importance in treatments in the future.”
