New research published in The BMJ highlights important differences in thrombotic risks associated with different forms of menopausal hormone therapy (MHT).
In a Danish national study, oral MHT was associated with increased rates of venous blood clots, while the risks of ischemic stroke and myocardial infarction (heart attack) varied by dose and duration. Transdermal therapy had a much better safety profile, minus a higher risk of heart attack when using combined cyclic therapy (hazard ratio (HR), 2.1; 95% CI, 1.1-4.1).
“The risk profile of different preparations is truly complex, as our study shows,” said Amani Meaidi, MD, PhD, a physician and research group leader in the department of gynecology and obstetrics at Copenhagen University Hospital in Denmark and an author of the study. “What matters is that we remain evidence-based and continue to refine our understanding of the risk profile of hormone therapy, so that women can make their own informed assessment of the benefits and risks, rather than swinging like a pendulum from one paradigm to another.”
Compared with no current hormone therapy, oral HRT (alone or with a progestin) was associated with a 60% higher rate of blood clots (HR, 1.6; 95% CI, 1.5-1.8), a 30% higher rate of stroke (HR, 1.3; 95% CI, 1.2-1.4), and a 30% higher rate of stroke (HR, 1.3; 95% CI, 1.2-1.4), and heart attack 20% higher (HR, 1.2; 95% CI, 1.1-1.3).
Compared to no hormone therapy, the risk of blood clots was increased depending on the doses and duration of treatment. An exception was oral estradiol combined with levonorgestrel.
Low-dose oral estradiol was not associated with an increased risk of stroke or heart attack of any duration. Using higher doses for more than a year actually increased these risks.
The researchers used data from the Danish National Health Register from 2003 to 2021 on women aged 50 to 69. Women with a history of venous or arterial thrombosis, cancer, liver disease, thrombophilia, oophorectomy, infertility treatment, endometriosis, or polyendocrine ovarian metabolic syndrome were excluded.
The researchers identified 9,807 women with a first venous blood clot, 18,460 with a first stroke, and 11,974 with a first heart attack. Each case was matched by year of birth with five women who had not experienced this outcome at that time. Prescription records were used to determine current MHT use, including route, dose, and duration.
Despite the increase in relative risk, the absolute increases were small: oral MHT was associated with approximately nine additional blood clots, six strokes, and three myocardial infarctions per 10,000 women per year.
“These absolute numbers show that thrombotic events remain a rare side effect of oral hormone therapy,” Meaidi said. But because MHT is widely used and these events can be fatal, “even a small absolute risk translates into a significant number of events at the population level,” she said.
The risks must be considered in the context of each patient’s cardiovascular and thrombotic risk and weighed against the potential benefits of MHT, said Michael Solotke, MD, clinical assistant professor in the department of obstetrics and gynecology at the Feinberg School of Medicine in Chicago, who was not associated with the study.
Meaidi said the research offers clinicians guidance for balancing risks with the need to effectively treat symptoms.
“Our results support an individualized approach: when oral treatment is appropriate, clinicians should consider using the lowest effective dose, ideally a maximum of 1 mg of estradiol per day, and regularly reevaluate the need for treatment,” Meaidi said.
But “although 1 mg is a common oral dose of estradiol, it is not uncommon for patients to have inadequate symptom control at this dose, so they may increase to a dose >1 mg,” Solotke said. The study data should not be interpreted as showing causation, but it provides useful information to incorporate when discussing higher oral estradiol doses with patients, he said.
In a companion opinion piece, Meaidi cautioned against letting the growing enthusiasm for MHT stray too far from the fears that have surrounded the treatment for decades.
“It is the responsibility of the clinician, when treatment is necessary, to recommend not only the most effective option, but also the safest, rather than reducing the conversation to a simple ‘safe or unsafe’ label,” she said.
Brittany Vargas is a freelance journalist covering medicine, mental health and wellness.
Meaidi said he received a speaking fee from Astellas. Solotke reported no disclosures.
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