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What is the topic?
Data from two very large studies -- the HERS trial (for Heart and Estrogen/Progestin Replacement Study) and the Women’s Health Initiative -- have raised questions about the use of hormonal replacement therapy (HRT) for women during menopause; those studies seemed to show that HRT increases a woman’s risk for heart disease. This is of even greater concern for women with lupus, because lupus puts women at higher risk for heart disease. The use of HRT by women with lupus raises other issues as well, since the sex hormone estrogen has been shown to play a role in the development of lupus in mouse studies and also may contribute to increased disease activity.
On the other hand, data from two large studies published in 2005 (OC-SELENA and HRT-SELENA) suggested that estrogen supplementation could be used safely by women with lupus with minimal, if any, significant increase in flares.
What did the researchers hope to learn?
Two different groups of researchers have recently published additional studies to find out if HRT during menopause was safe for women with lupus. One of the studies, conducted in Mexico, was to see whether HRT increased lupus disease activity. The second study, which used records from the LUMINA database (LUpus in MInority populations: NAture vs. nurture) in the United States and Puerto Rico, looked specifically for connections between HRT and heart or blood vessel disease, also known as cardiovascular (CV) disease, in women with lupus.
Who was studied?
The Mexican research study followed 106 women with lupus who were in menopause. To participate, the women had to have mild-to-moderate lupus and could not be over 65-years old. Since the study was conducted at one center in Mexico, it is likely (though not detailed in the study) that almost all the women in the study were Mexican.
In the study using data from LUMINA, the researchers examined the records of 72 women with lupus during the period when they were entering or in the early years of menopause. Thirty-two of the women had used HRT; 40 did not use HRT. The women in the LUMINA study resided in Alabama, Texas, Puerto Rico, and were from different ethnic groups (Hispanic -- from Texas, primarily of Mexican or Central American ancestry, and from the Island of Puerto Rico; African American; and Caucasian) with women from each of the groups among the HRT users and non-users. Because the study was focusing on CV risks, the researchers did not include women who had antiphospholipid antibodies (aPL), which have been associated with a separate risk for blood clots. Including them in this study might cause a confusing picture by adding additional risk factors for heart or blood vessel-related outcomes.
How were the studies conducted?
In the Mexican study the women were divided into two groups. One group received a standard course of HRT medicine (a mix of estrogen and progestin hormones) for the first 10 days of every month. The other group received placebo (pills that looked exactly the same as the HRT medicine but which had no active ingredients). The placebo group took these pills according to the same schedule as the other group took their HRT medicines. The women’s health status was followed for two years to track their overall lupus disease activity, flares, and any significant organ involvement.
The study using information from the LUMINA database looked at medical records that had been collected for years. The researchers noted the number of CV events among women who used HRT and those who didn’t, and classified those events as either "arterial" (related to the arteries, which carry blood with oxygen from the heart to the tissues) or "venous" (related to the veins, which carry blood back to the heart ). Heart attacks, angina, stroke, cardiac bypass surgery, blockages, or hardening of the arteries were taken as indications of arterial events. Clots in the veins (thrombosis) were an indication of venous activity. The researchers then used a series of statistical methods to compare characteristics of the HRT users and non-users (such as their age, ethnic background, smoking habits, severity of their lupus, lupus medications, and family history of heart disease) to try to rule out other factors that might account for differences in CV events, which could potentially cloud the understanding of the outcomes.
What did the researchers find?
In the study done in Mexico, the researchers found no significant difference in most of the outcomes between the women who took HRT medicine and those who took the placebo. In both groups, lupus disease activity remained mild and stable over the 24 months; the percentage of women who had flares was about the same (44% of the HRT users versus 39% for the placebo group), as was the amount of time that elapsed before the first flare (three months for both groups).
The only area where there was a significant difference was in CV events: three HRT group members experienced blood clots (one venous, two arterial) and one placebo group member had an arterial CV event. This suggested to the researchers that HRT use could further increase the risk of thrombosis for women with lupus, who are already at much greater risk than women in the general population. However, since the total number of events was so small, this speculation was not proven, and may not be significant.
In the LUMINA-based study, the researchers found that 13 women had arterial events (2 HRT users, 11 non-users) and 8 had venous events (3 HRT users, 5 non-users). After taking other factors into consideration, the researchers concluded that HRT use did not increase the risk for CV events, either arterial or venous. As a result, they suggested that for women with lupus who do not have aPL antibodies, HRT may provide benefit without raising the risks of cardiovascular disease.
What were the limitations of the studies?
The strengths of the design of the Mexican study included the fact that the women taking hormones could be directly compared, over time, to those with comparable disease who were taking a placebo. Also, by collecting the data over time instead of just reviewing records, more complete and accurate information was obtained. An additional strength of the study was the "blinding" (keeping information from the participants and the study staff about who was getting the HRT medicine and who was not); blinded studies produce very good data by avoiding any bias in the assessment of disease activity or other outcomes by either the doctor or the study participant.
However, because all of the women in the study were from one center in Mexico and probably of similar ethnic background, the findings may not be indicative of how HRT use might affect women from other ethnic groups common to the U.S. (Caucasians, African Americans, Asian Americans, or Native Americans). Also, the study used only one particular HRT combination, so it is not known whether other HRT formulas would produce the same results.
The LUMINA-based study had different limitations. First, the researchers only used information that had been collected in the past, so they might not have had all the information they would have wanted to collect. For instance, they weren’t able to determine exactly how long each person had been using HRT, or the dose or drug mixture. Second, the researchers were not able to balance the make-up of the two groups, so Caucasians were overrepresented among the HRT users, and African Americans were overrepresented among the non-HRT users.
Additionally, both of the studies had relatively small numbers of participants, which limits the conclusions that can be drawn about how HRT use affects women with lupus.
What do the results mean for you?
The use of hormones by women with lupus, as contraceptives or to treat conditions that arise during menopause, has raised concerns. These two studies seem to indicate that use of HRT during menopause, especially in low doses, could provide benefits for some women with lupus without raising their short-term risk of cardiovascular disease. Added to the earlier data collected from the large, prospective SELENA studies and an earlier study from Mexico (also published in 2005), women with lupus and their doctors can have increased confidence that under the right clinical conditions, at least for the short term, the choice of HRT may be a reasonable one.
From the Lupus Foundation of America
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