For millions of women, the symptoms of genitourinary syndrome of menopause (GSM) are an accepted but deeply disruptive part of aging. Vaginal dryness, irritation, pain during sex, recurrent vaginal and urinary tract infections, and urinary symptoms can affect daily life, relationships, and wellbeing. Yet, the condition remains widely underdiagnosed and undertreated.
While over-the-counter lubricants and moisturizers can offer temporary relief, they do little to address the biological changes caused by declining estrogen levels. Local estrogen therapies are considered one of the most effective treatments for GSM, but concerns surrounding the potential cancerous effects of hormone therapy can discourage many women and clinicians from using them.
Now, researchers at the University of Colorado Anschutz Medical Campus have developed a potential alternative that aims to restore the health of vaginal tissue without relying on conventional steroid hormones. Published in Menopause, the team describe a synthetic flavone, known as 3-fluoro 6,4'-dihydroxyflavone (3F), that regenerated the vaginal epithelium in a preclinical model while showing no evidence of systemic estrogenic activity.
Beyond treating dryness
Although GSM is commonly associated with vaginal dryness, the condition extends far beyond inadequate lubrication. Estrogen deficiency fundamentally alters the biology of the vaginal lining, leaving tissues thinner, more fragile, and increasingly vulnerable to injury and infection.
"Over-the-counter methods for treating lubrication may provide enough relief to ease some symptoms, such as pain during intercourse," Steve Nordeen, pathologist at the University of Colorado Anschutz School of Medicine and senior author of the study, told DDN. "However, they don't address the degenerative changes in the vaginal epithelium."
As estrogen levels decline, the protective epithelial lining becomes more susceptible to tearing, increasing discomfort while also raising the risk of vaginal infections. The condition is also accompanied by changes in vaginal pH, disruption of the microbiome, and reduced production of naturally protective molecules, including antimicrobial proteins such as lactoferrin and defensins, as well as mucins that help lubricate tissue and trap invading pathogens.
Nordeen explained that estrogen deficiency also disrupts the normal maturation of epithelial cells. As fewer mature cells are produced and shed, less glycogen becomes available to support beneficial Lactobacillus species, allowing vaginal acidity to decline and potentially enabling harmful bacteria to flourish. These changes contribute to the increased risk of vaginal infections frequently seen in postmenopausal women.
Hormone replacement therapies, whether delivered systemically or locally, can reverse many of these changes by restoring estrogen signaling. However, many patients are hesitant to use them because of concerns about potential links to hormone-sensitive cancers.
Women receiving estrogen-suppressing therapies for hormone receptor-positive breast cancer may be particularly affected. While these treatments are highly effective against cancer, reducing estrogen levels can also trigger severe GSM symptoms, leaving some patients with few effective treatment options they feel comfortable using.
"Estradiol is an extremely potent estrogen," Nordeen said. "Many patients, particularly those with breast cancer or a family history of breast cancer, are reluctant to use steroidal estrogens, which is one reason we wanted to develop an alternative with built-in safeguards."
Mimicking estrogen where it matters
Rather than replacing estrogen itself, the researchers designed 3F to activate the same signaling pathway within vaginal tissue while minimizing exposure elsewhere in the body. The compound has multiple properties that allow for this. For example, it has a much lower affinity for estrogen receptors than estradiol and is rapidly metabolized by the liver once it enters circulation. Additionally, the compound is administered as a vaginal suppository to further mitigate systemic exposure.
"If you can achieve sufficient local concentrations while suppressing systemic accumulation, the potential for estrogenic stimulation of tissues such as the breast is minimized," Nordeen said.
An additional advantage is their established safety profile. “We consume flavonoids every day in our diets," he added.
In ovariectomized rats, vaginal delivery of 3F restored the thickness and differentiated structure of the vaginal epithelium to levels comparable with estradiol treatment. The compound also restored production of lactoferrin, an antimicrobial protein that helps protect against infection.
Importantly, however, the researchers found that tissue regeneration occurred without stimulating cell proliferation. "The potential danger of estrogen therapy is its ability to stimulate cell proliferation in some tissues," Nordeen said. "Showing that, in the vagina, estrogen signaling appears to promote proper differentiation and maturation of the epithelium rather than proliferation is quite important."
An unexpected finding
While the restoration of vaginal tissue was anticipated, one result surprised the researchers. "We showed that the flavone stimulated mucin production remarkably, whereas estradiol alone did little to increase mucins," Nordeen said.
Mucins form a protective mucus layer that lubricates vaginal tissue while also helping defend against infection. Their loss contributes to many of the symptoms experienced by women with GSM. "Mucin production is vital to the restoration of proper vaginal function and relief of symptomology," Nordeen said.
The team is still investigating why 3F outperformed estradiol in stimulating mucin production. One possibility is that the observation reflects species-specific biology in the rat model, although Nordeen believes other explanations, including differences in dose response, remain plausible.
Crossing the valley of death
Although these findings demonstrate proof of concept, considerable work remains before 3F can be evaluated in patients. Animal studies cannot fully predict human biology, and the researchers acknowledge that clinical development will require substantial additional investment.
"We are in the so-called 'valley of death' stage between solid proof of concept and investigational drug approval from the FDA," Nordeen said. "This is where drug development often dies because of the cost to meet regulatory requirements."
Securing those resources may prove especially challenging in women's health, an area that is well-known for receiving insufficient commercial attention despite affecting half of the population. A 2026 report by the World Economic Forum found that only six percent of private healthcare investment was directed toward women's health.
Nordeen also hopes the work will help reinforce that GSM is a treatable medical condition, rather than an inevitable consequence of aging. If future clinical studies confirm the preclinical findings, he believes 3F could offer a new option for women seeking to restore vaginal health without conventional steroid hormones, potentially expanding treatment options for the millions of women living with GSM.
