By Steven Fein, MD, MPH
For many women, the decision to start estrogen-containing hormone replacement therapy (HRT) or oral contraceptives (OCPs) is a pivotal health moment.
These medications can be life-changing. They regulate cycles, prevent pregnancy, relieve perimenopausal and menopausal symptoms, and protect bone health. For millions of women, estrogen improves quality of life.
But estrogen is not risk-free.
One of the most important considerations is the risk of developing blood clots, including deep vein thrombosis (DVT), pulmonary embolism (PE), or stroke. While the overall risk is low for most healthy women, it is not the same for everyone.
The difference often lies in your genetics.
Hereditary Thrombophilia: The Hidden Variable
Some individuals carry inherited genetic variants that increase their tendency to form blood clots, a condition known as hereditary thrombophilia.
The two most common variants are Factor V Leiden (F5 gene) and Prothrombin G20210A (F2 gene). These variants are common. Approximately 1 in 20 people of European ancestry carries one of them.
To put this in perspective, the baseline annual risk of a serious blood clot is roughly 1 in 1,000. Carrying one of these variants can double that risk. When estrogen is added, particularly oral estrogen, the risk can increase substantially, in some cases several-fold higher than baseline.
Without genetic information, we are estimating risk.
With genetic information, we are personalizing it.
What About MTHFR?
Another gene that has been proposed to be a hereditary clotting risk factor is the MTHFR gene. Some studies have suggested an increased risk of blood clots in individuals who carry two copies of the C677T variant, while others have found no clear association.
Because the evidence is mixed, genetic results should be interpreted with caution. However, knowing your status can still be informative: if you carry these variants, a simple blood test to measure homocysteine levels may help clarify your overall risk profile and guide further discussion with your clinician.
Genetics Is Only Part of the Picture
While your tendency to develop blood clots is primarily determined by genes, life events and circumstances are also important. The most widely recognized DVT and PE risks are injuries, surgeries, and long airplane flights (more than four hours long). Cigarette smoking and hypertension are risks for developing stroke.
Estrogen is a mild pro-thrombotic factor (a factor that increases the likelihood of forming a blood clot), whether during pregnancy or through hormone therapy.
The key question is not “Is estrogen safe?”
The key question is “Is estrogen safe for you?”
Risk Mitigation Is Possible
If a woman carries a clotting-risk variant, that does not automatically mean she cannot take estrogen.
Instead, it opens the door to informed strategies such as choosing transdermal estrogen, which carries lower clot risk than oral formulations, using low-dose aspirin while taking estrogen, short-term anticoagulation during high-risk periods (e.g., surgery or long travel), or close clinical monitoring.
Knowledge allows preparation. Preparation reduces fear.
The Role of 23andMe in Understanding Your Genetic Risk
This is where resources like 23andMe become invaluable. They provide easily understandable and reliable access to important genetic information related to blood clotting, empowering both patients and physicians.
The 23andMe Hereditary Thrombophilia report* specifically includes analysis for the two most common variants linked to hereditary thrombophilia: factor V Leiden and prothrombin G20210A. 23andMe also offers a report that includes MTHFR variants.
Why I Recommend 23andMe for My Patients
As a hematologist specializing in women’s health hematology, I frequently discuss genetic clotting risk with patients who are planning pregnancy or considering estrogen therapy.
In recent years, many insurance carriers have stopped covering inherited thrombophilia testing. Instead, direct-to-consumer genetic testing platforms like 23andMe have made validated variant testing more accessible and affordable. For appropriate patients, it can provide clinically useful information that guides safer, more confident decision-making.
Personalized Medicine Is Not the Future-It’s the Present
Understanding your genetic profile allows your physician to contextualize your clotting risk, weigh the benefits and risks of estrogen therapy, and develop individualized risk-mitigation strategies.
This is personalized medicine in action!
Before starting estrogen therapy, have a conversation with your physician about your family history, personal risk factors, and whether genetic testing may be appropriate for you. In some cases, it may also be helpful to consult a hematologist who has expertise in women’s health.
Because when it comes to your health, guessing is no longer necessary.
About Steven Fein, MD, MPH
Dr. Steven Fein is a board-certified hematologist with more than 20 years of clinical experience. He received his medical degree from Johns Hopkins School of Medicine, completed residency training in internal medicine at Duke University Medical Center, and completed a fellowship in hematology and oncology at the University of Miami Miller School of Medicine.
In 2020, he founded Fem Women’s Health, a nationwide telemedicine hematology practice dedicated to caring for women with clotting disorders, bleeding conditions, or iron deficiency.
This post reflects the personal insights and opinions of Dr. Fein. It does not necessarily represent the views of 23andMe. We appreciate the unique perspective shared here.
* The 23andMe PGS test uses qualitative genotyping to detect clinically relevant variants in the genomic DNA of adults, from saliva collected using an FDA-cleared collection device (Oragene·DX model OGD-500.001) for the purpose of reporting and interpreting genetic health risks. The relevance of each report may vary based on ethnicity. Our genetic health risk reports describe if a person has variants associated with a higher risk of developing a disease, but do not describe a person’s overall risk of developing the disease. The reports are not intended to diagnose any disease, tell you anything about your current state of health, or to be used to make medical decisions, including whether or not you should take a medication or how much of a medication you should take. The Hereditary Thrombophilia genetic health risk report (i) is indicated for reporting of the Factor V Leiden variant in the F5 gene, and the Prothrombin G20210A variant in the F2 gene, (ii) describes if a person has variants associated with a higher risk of developing harmful blood clots, and (iii) is most relevant for people of European descent.
