Heavy Menstrual Bleeding Shares Genetic Risk with Endometriosis and Fibroids

Study identifies new genetic link between heavy menstrual bleeding and endometriosis.

Key Points

Highlights: 

• There was a strong genetic association between heavy menstrual bleeding (HMB) and endometriosis, uterine fibroids, and ovarian cysts.
• Strong genetic correlations were observed between HMB and other gynecologic conditions such as endometriosis, uterine fibroids, and ovarian cysts.

Importance:

• This is the largest multi-ancestry genetic study to date on HMB, providing critical insight into its etiology and biological pathways.
• Newly discovered loci may guide the development of targeted therapies for HMB and related gynecologic disorders.

What’s done here:

• The study meta-analyzed Genome Wide Association (GWAS) summary statistics from five large biobanks, comprising 84,633 HMB cases and 598,195 controls across multiple ancestries.
• Researchers combined discovery and replication datasets to detect genome-wide signals and used gene prioritization tools (such as TWAS and PoPS) to identify likely causal genes.

Key results:

• A total of 36 independent loci were associated with HMB; 20 signals were directionally concordant across cohorts, and 10 reached replication significance.
• The F5-Leiden variant (rs6025-T) had a strong protective effect against heavy menstrual bleeding.
• Significant variants were found near follicle-stimulating hormone subunit beta (FSHB) and human luteinizing hormone/chorionic gonadotropin β (LHB/CGB) loci, both implicated in hormone regulation.
  Several signals were linked to genes involved in the Wnt/β-catenin signaling pathway, known to regulate endometrial growth.
• HMB showed significant genetic overlap with disorders of the female reproductive tract, particularly endometriosis, suggesting shared biological mechanisms.

From the Editor-in-Chief – EndoNews

"This study represents a critical step forward in unraveling the complex biology behind heavy menstrual bleeding—a symptom often dismissed, underreported, or treated without clear understanding of its origins. The discovery of 33 novel genetic signals, alongside strong overlaps with endometriosis and other gynecologic disorders, reinforces that HMB is not merely a clinical inconvenience but a condition with deep biological roots and broad reproductive health implications.

The strength of this research lies not only in its scale, but in its multi-ancestry design and integration of advanced gene prioritization tools. As we move toward more precise and individualized care in women’s health, these findings provide a foundation for rethinking how we diagnose, classify, and treat menstrual disorders that have long been overlooked in mainstream medicine."

Lay Summary

Heavy menstrual bleeding (HMB) is a common yet underexplored condition affecting millions of women worldwide. It can severely impact quality of life and is often associated with other gynecologic disorders like endometriosis and fibroids.

In a recent landmark study published in Blood, researchers led by Dr. Andrew D. Johnson at the National Heart, Lung, and Blood Institute conducted the largest genetic study of HMB to date, involving over 84,000 cases and 598,000 controls from five biobanks across multiple ancestries.

Through the analysis of genome-wide association studies, they identified the loci associated with heavy menstrual bleeding. Using gene prioritization techniques such as transcriptome-wide association studies and polygenic priority scores, the researchers identified gene variants that were likely causing heavy menstrual bleeding. 

The study identified 36 genetic loci associated with HMB, 33 of which were novel. In other words, women who have these versions of the chromosomal regions are at an increased risk of experiencing heavy menstrual bleeding.

One particularly notable finding was the strong protective effect of the F5-Leiden variant (rs6025-T), a common mutation in the clotting pathway.

Additional signals were detected in regions linked to hormonal regulation (FSHB, LHB/CGB loci) and in pathways controlling endometrial growth, such as the Wnt/β-catenin signaling pathway.

Beyond individual genes, the researchers found a significant shared genetic architecture between HMB and other reproductive disorders, including endometriosis, uterine fibroids, and ovarian cysts. 

These findings not only deepen our understanding of the biology underlying HMB but also open new avenues for therapeutic development and cross-condition research.

Research Source: https://pubmed.ncbi.nlm.nih.gov/40324064/