Hormone Replacement Therapy- What did the JAMA Study really

Hormone Replacement Therapy- What did the JAMA Study really show?
Harold J. DeMonaco, MS, Director of Drug Therapy Management
Volume XII, Issue 6

By now, most of you have heard from your patients about the recent study published in JAMA.¹ Many have likely read the manuscript and accompanying editorial and formed an opinion on the merits of the conclusions.

The NIH-sponsored study entitled Risks and benefits of estrogen plus progestin in healthy postmenopausal women was intended to examine the health effects of hormone replacement therapy (HRT). Prempro (a combination of 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate) was the test drug in this placebo-controlled trial. A total of 16,608 women between the ages of 50 and 79 years were enrolled in the HRT arm of the study. Women without an intact uterus were entered into a study comparing the health effects of estrogen replacement alone (ERT), without progesterone. The HRT study was stopped at a mean of 5.2 years of follow-up by an independent data and safety monitoring committee because the incidence of breast cancer in the treated group exceeded the predetermined stopping points. Overall, the risks of HRT (using Prempro) exceeded the benefits.

The absolute risks identified in the study associated with the use of Prempro (per 10,000 person-years) were:

7 additional cardiac events
8 additional strokes
8 additional cases of pulmonary embolism
8 additional cases of invasive breast cancer

However, there were some advantages to HRT. They were:

6 fewer cases of colorectal cancer
5 fewer cases of hip fracture

The results are disturbing to say the least, but need to be taken in context:

It is important to note that most of the risks of HRT with estrogen/progestin begin within 1-2 years of therapy. Breast cancer risk, however, does not start to increase until year 4 of therapy.
A previous study has suggested that estrogen/progestin replacement may carry a higher risk of breast cancer than estrogen alone.²
The absolute risk for any given patient is very small.
Subgroup analysis suggested that age was not an important variable.
The Data and Safety Monitoring Committee did not stop the parallel estrogen replacement therapy arm of the study. So the health benefits/risks of ERT may not be the same as for HRT.

What do we tell patients? Here are some thoughts:

The long-term use of estrogen and progesterone in these doses should be questioned. Short-term use for less than one year carries with it a slight increase in cardiovascular risk. This risk needs to be balanced against symptom relief.
While it is unclear if a lower dose of HRT would reduce risk, using the lowest possible dose of estrogen and progestin makes sense. There are data to suggest a half-dose regimen (0.3mg of conjugated estrogen and 1.5mg of medroxyprogesterone) is effective in reducing symptoms and risk of osteoporosis.³
At the moment the health benefits/risks of estrogen replacement for women without an intact uterus are unclear. Conjugated estrogen 0.3mg has been shown to reduce vasomotor symptoms in many women and improve bone mineral density, although the effect of such doses on fracture risk is not defined.

References: