Lower Doses of Estrogen in Hormone Therapy Carry Less Cardiovascular Risk

Fran Lowry

October 13, 2010

October 13, 2010 (Chicago, Illinois) — Lower doses of estrogen, when used in estrogen plus progestin hormone formulations, such as the transdermal patch, for the treatment of menopausal symptoms are associated with a significantly reduced risk for cardiovascular events, according to research presented here at the North American Menopause Society (NAMS) 21st Annual Meeting.

Using the lowest effective dose for the shortest duration necessary is the new mantra for the management of symptoms associated with menopause, researchers said at the meeting.

"Hormone-therapy-prescribing guidelines have changed since the results of the Women's Health Initiative [WHI] clinical trials, diverging from treatment directed at chronic disease prevention to treatment directed at menopausal symptom management," said Chrisandra L. Shufelt, MD, assistant director of the Women's Heart Center at the Cedars-Sinai Heart Institute in Los Angeles, California.

New low-dose formulations of estrogen have become available, but research on the relation between these lower doses and cardiovascular disease outcomes has been limited, she said.

Dr. Shufelt and her team decided to analyze the relation between estrogen dose and coronary heart disease risk, stroke, and venous thromboembolism in the WHI observational study of nearly 94,000 postmenopausal women. Low-dose estrogen was defined as less than 0.625 mg, conventional-dose or standard estrogen was defined as 0.625 mg, and high-dose estrogen was defined as more than 0.625 mg.

The women were 50 to 79 years of age at study entry and were recruited between September 1993 and December 1998. They were followed annually until February 28, 2003, and were asked about their use of hormone therapy at each follow-up visit.

Of the cohort, 17,503 (19%) were taking estrogen plus progestin hormone therapy and 21,902 (23%) were taking estrogen alone. The vast majority of the women (15,169) who used estrogen plus progestin were taking the conventional dose, 1,258 (7%) were taking low-dose estrogen, and 1,076 (6%) were taking high-dose estrogen.

Among women who took estrogen alone, 941 (4%) were taking low-dose and 2,567 (12%) were taking high-dose estrogen.

The average length of follow-up for these analyses was 5.5 years.

The study found a 71% lower risk for coronary heart disease and a 69% lower risk for venous thromboembolism in women who used low-dose estrogen in their estrogen plus progestin hormone therapy than in those who used conventional-dose estrogen. The risk for coronary heart disease was more than 2-fold higher in women who used high-dose estrogen in the estrogen plus progestin formulation, Dr. Shufelt reported.

The dose of progestin did not appear to be linked to cardiovascular events.

Also, there was no significant relation observed between the dose of estrogen and cardiovascular events in women who used estrogen alone, she said.

"Our study is consistent with other recent publications that have found that transdermal estrogens may have a less adverse effect in terms of cardiovascular risk, both arterial and venous," Dr. Shufelt told Medscape Medical News. "However, further research is needed to provide conclusive evidence that will help form clinical decision making on menopausal symptom management in clinical practice."

"This report is valuable in that it provides some information about low estrogen doses. We don't have a lot of information about low-dose estrogen and whether or not it is truly safer," said Margery L.S. Gass, MD, executive director of NAMS and consultant at the Cleveland Clinic in Ohio.

People have believed lower estrogen doses to be safer for hormone replacement therapy because of previous experience with other preparations, such as birth control pills, she told Medscape Medical News.

"When we were using really high birth-control-pill doses, there were more side effects. But the side effects decreased dramatically with lower doses," Dr. Gass said. "As the doses got lower and lower as the years went on, the pill became safer and safer. So such examples have made people think that lower doses of hormone therapy will follow a similar pattern. This study provides some evidence in that regard."

Dr. Shufelt and Dr. Gass have disclosed no relevant financial relationships.

North American Menopause Society (NAMS) 21st Annual Meeting: Abstract 64. Presented October 8, 2010.

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