Hypothesis disproved on uterine fibroids and elevated nerve activity, other fibroid relationships uncovered

July 11, 2023

Though researchers discovered a link between uterine fibroids (UF) and hypertension back in the 1980s, few people have heavily researched the connection and the question of why this relationship might exist over the following decades, according to Ronée Harvey, M.D., Ph.D., a postdoctoral research fellow in Anesthesia Research at Mayo Clinic in Minnesota.

"It's taken a while to get people's attention to women's health topics in general," says Dr. Harvey. "However, in the last 15 to 20 years, women's health has taken off. The National Institutes of Health started the Office of Research on Women's Health in the 1990s. Interest has grown in researching women's health topics such as the link between uterine fibroids and hypertension."

UF and high nerve activity hypothesis debunked

Medical researchers speculated nerve activity was key to the UF and blood pressure link, according to Dr. Harvey. She and a team of investigators in the Human and Integrative Physiology and Clinical Pharmacology Laboratory at Mayo Clinic decided to look further into the connection. Other studies had demonstrated muscle sympathetic nerve activity (MSNA) caused both hypertension and the risk of hypertension, as evidenced in a 2020 publication in American Journal of Hypertension by Yoshitaka Hirooka. Thus, the Mayo Clinic team theorized that even if women with UF were not currently experiencing elevated blood pressure, they might show signs of high nerve activity.

What Dr. Harvey and team found contradicted the team's hypothesis.

"We found that women who had uterine fibroids did not have high nerve activity," says Dr. Harvey. "That was not our hypothesis, but yet we feel like this is good news. If women with uterine fibroids did not have other comorbidities, their risk of high blood pressure was not different than women without uterine fibroids."

Unique MSNA and systemic hemodynamic relationships discovered in women with UF

Yet, Dr. Harvey and team found vascular distinctions between the study group with UF and those without fibroids. They found a positive correlation between total peripheral resistance and MSNA (r = 0.75, p = 0.02) in the women who had UF. Additionally, they discovered cardiac output was negatively correlated with MSNA in the women with UF (r = -0.73, p = 0.03). These interactions did not exist for the women in the study who did not have UF (p > 0.05 for both relationships).

"These data suggest that autonomic interactions with systemic hemodynamics, and thus blood pressure regulation, are different in healthy women with UF compared to healthy women without UF," the authors explain in the publication, which appeared in a September 2022 issue of Physiological Reports.

Researcher insights on the study findings

Dr. Harvey considers this study novel because no one had looked at the sympathetic nerve activity in this population of women with and without UF. The research intentionally focused on premenopausal women due to the higher risk in postmenopausal women for elevated blood pressure and sympathetic nerve activity, says Dr. Harvey. The researchers wanted to determine these mechanisms for women in their late 30s to 40s. Fibroids also can become inactive in menopausal women, she says, especially due to estrogen levels, making premenopausal women more ideal subjects for this study.

"We wanted to focus on risk factors for cardiovascular disease and for fibroids," says Shannon K. Laughlin-Tommaso, M.D., a gynecologist and obstetrician at Mayo Clinic's campus in Minnesota and a study author. "I appreciate this study because cardiovascular disease is the leading cause of death for women in the United States. So, looking at the link between cardiovascular disease and uterine fibroids is important."

Dr. Harvey notes that one upside for study participants without UF — or who had not noticed any UF symptoms — is the opportunity to rule out the presence of UF through imaging.

How the investigators designed the study

The researchers created a cross-sectional study design, looking at each participant and the measurements from testing one at a time. Dr. Harvey says this type of design is positive for participants, as they can complete the study requirements fully in two visits. The investigators' intentions were to test each participant's MSNA plus blood pressure at baseline. Each participant completed what Dr. Harvey calls a "quite extensive study including invasive portions" for a screening day and an experimental study day, including transvaginal ultrasound, blood pressure measurement with an arterial catheter, electrocardiogram and microneurography, among other tests.

The downside of this study design is that it does not involve following the subjects over time to see if they develop hypertension, says Dr. Harvey. She explains, however, that sometimes patients become lost to follow-up in a longitudinal study. This study involved 23 individuals — 14 healthy women without hypertension who had UF, and nine healthy women without hypertension or UF. Dr. Harvey says this is a typical sample size for physiological studies the lab conducts.

"We were particularly happy with the number of participants that we could recruit for the study who had no comorbidities and who took no medications outside of supplements or oral contraceptives," says Dr. Harvey. "Participants like this can be difficult to find."

Study continuation in search for further answers

Despite the answers they derived from the study published in Physiological Reports, the hypertension typical in female patients diagnosed with UF still troubled the Mayo Clinic investigators. So, Dr. Harvey and team have started a continuation of the study to better understand this link. The team is looking at sympathetic nerve activity, scrutinizing how women's UF relates to stress and focusing on physical stressors.

"Even if women do not have hypertension in the moment, their blood pressure usually increases when placing their hand in a bucket of ice water," says Dr. Harvey. "This is an example of what we've observed: Individuals who have greater sympathetic nerve activity and blood pressure reactivity to stressors have a greater risk of hypertension."

The research team is currently determining if women with UF have exaggerated responses to stressors in comparison to women without UF. Team members are making observations while they place ice packs on participants' foreheads for three minutes.

Why the focus on UF

Dr. Harvey and Dr. Laughlin-Tommaso feel the study of UF is critical because the condition significantly affects a large percentage of women — up to 1.4 higher odds of hypertension in women with UF, according to a 2022 publication in Hypertension Research. Dr. Laughlin-Tommaso indicates that 35% of women who have UF experience what fibroid specialists consider major symptoms: heavy menstrual bleeding, pain in the abdomen, painful bowel movements and even fertility issues. She says that according to a study by Elizabeth A. Stewart, M.D., a gynecologist and reproductive endocrinologist at Mayo Clinic in Minnesota, women with symptomatic fibroids will even change their jobs to be at home on symptomatic days. Dr. Stewart is also a fellow author on the Physiological Reports publication.

"Fibroids can really disrupt quality of life," says Dr. Laughlin-Tommaso.

Funding for the study published in Physiological Reports came from an American Heart Association award for predoctoral fellowship and funding came through the Center for Clinical and Translational Science at Mayo Clinic to conduct the studies in the Clinical Research and Trials Unit.