A study of postmenopausal individuals suggests that a hormone test could help identify biological changes associated with endometrial cancer risk before symptoms appear, paving the way for future screening strategies.
Endometrial cancer is the most common gynaecologic cancer in Canada, and its incidence continues to rise. Most cases are diagnosed only after symptoms develop, which is most commonly abnormal vaginal bleeding. There are currently no screening tests for endometrial cancer and no widely used approaches to identify individuals at elevated risk before symptoms occur.
Vancouver Coastal Health Research Institute (VCHRI) researchers Drs. Aline Talhouk and Andrea Neilson are exploring whether it is possible to identify people at increased risk long before cancer symptoms are present. Their study focused on postmenopausal individuals with obesity, a population at particularly high risk for developing endometrial cancer.
[inline image: Aline Talhouk][caption: Dr. Aline Talhouk is an assistant professor in the Department of Obstetrics and Gynaecology at the University of British Columbia, director of data science and informatics at OVCARE and director of the Uterine Health Research Lab.]
“Rather than waiting for symptoms to appear, we want to move further upstream and focus on prevention,” says Talhouk. “Cancer develops through a series of biologic changes, and if we can identify those changes, we may have an opportunity to intervene earlier.”
Published in Cancer Prevention Research, the study evaluated the feasibility of the progesterone challenge test (PCT): a decades-old gynaecologic test that measures how the uterine lining, or endometrium, responds to hormones. In this test, individuals take a 10-day course of progestin medication and are monitored for withdrawal bleeding — menstrual-like bleeding that occurs after the medication is stopped.
A stress test for the uterus
The study focused on people who were at least three years past the last menstrual cycle. After menopause, ovarian hormone production declines, the lining of the uterus becomes thin and menstrual bleeding stops.
However, in some individuals, ongoing exposure to estrogen can continue to stimulate the uterine lining after menopause. This may occur through hormone therapy or through estrogen produced by adipose tissue, which is common in people with obesity. The PCT was designed to identify whether the uterine lining remains hormonally responsive despite menopause.
“If we can identify individuals at increased risk earlier, we may have a greater opportunity to prevent cancer from developing in the first place.”
Participants in the study completed the PCT, which involved a 10-day course of progestin prescribed by their family physician followed by self-monitoring for withdrawal bleeding. If bleeding occurred, the test was considered positive.
It is important to note that a positive test does not mean that someone has cancer. Instead, it suggests the uterine lining is behaving differently than expected after menopause and may indicate an increased risk of developing the disease in the future.
Researchers describe the PCT as a functional biomarker because it measures how the uterine lining responds to hormones, rather than looking for a specific molecular or genetic indicator of disease.
“As a functional biomarker, the PCT is similar to the stress test we do for the heart,” says Talhouk. “It tells us whether the uterus is still responding to hormonal stimulation in a way that would not normally be expected after menopause.”
[inline image: Andrea Neilson][caption: Dr. Andrea Neilson is a gynaecologic oncologist at Vancouver General Hospital and an investigator at the Uterine Health Research Lab.]
Of the 51 participants who completed the test, 16 had a positive test result and were referred for further evaluation. Follow-up biopsies identified endometrial proliferation or hyperplasia in several participants — findings that are associated with abnormal endometrial biology and may increase future risk of developing endometrial cancer. No cancers were detected.
“The aim of the PCT is not to find existing cancer, but rather but rather to identify individuals whose endometrium may be on a pathway toward disease and intervene before cancer develops,” says Neilson. “Results indicated that the test worked as expected.”
Building the foundation for future provincial prevention strategies
Alongside completing the PCT, participants also provided self-collected vaginal samples that are currently being analyzed for molecular and genetic signals associated with endometrial cancer risk. Ongoing research aims to identify molecular signatures in self-collected vaginal samples that correlate with PCT positivity and underlying endometrial biology, with the long-term goal of replacing hormonal testing with a simple, non-invasive test.
“The progesterone challenge test is one step toward helping us identify individuals at risk of the most common hormone-associated forms of the disease.”
Talhouk notes that the PCT has limits for widespread use. While most participants found it acceptable, some were hesitant about taking a 10-day course of progestins while feeling well, and others reported negative side effects such as mood changes or bloating. For these reasons, the test is best viewed as a stepping stone between current symptom-based care and future approaches to assessing endometrial cancer risk.
Researchers hope to translate these insights into simpler tools that could eventually be done without clinical visits, including self-collected tests similar to at-home screening kits already used for other gynaecologic cancers.
“This research is about targeting a highly preventable disease,” says Talhouk. “Ultimately, the goal is to leverage existing screening infrastructure and minimally invasive testing to identify risk earlier and reduce the incidence of endometrial cancer overall.”
This work was made possible with support from the Canadian Cancer Society and Canadian Institutes of Health Research.
