Systemic lupus erythematosus (SLE) is an autoimmune disease that primarily affects young women. Nonetheless, an increasing number of women with lupus now reach the postmenopausal stage because of their susceptibility to development of premature menopause, and because of the extraordinary improvement in the prognosis and survival rate (1, 2).
Menopause entails the risk of developing vasomotor and other symptoms, as well as chronic conditions, such as osteoporosis. Although menopause hormonal therapy is the most effective treatment for vasomotor and urogenital symptoms, the results of the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) trials, which showed that the risks outweigh the benefits (3, 4), dramatically altered the medical practices of such therapy (5). Despite a striking decrease in the use of menopause hormonal therapy, many women remain eligible for it. Current guidelines recommend menopause hormonal therapy at the lowest effective dose and for the shortest time necessary (6).
Several studies have established the relevance of sex hormones in SLE. Overall, these data suggest that estrogens favor the development and/or exacerbation of the disease, while androgens seem to be protective (7–17).
Although a high rate of SLE flares in women taking combined oral contraceptives has been reported (18), recently we and the investigators in the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) group published the results of 2 randomized clinical trials, which showed that estrogen-containing oral contraceptives did not increase the risk of SLE disease activity exacerbation (19, 20). Menopause hormonal therapy was safe, well tolerated, and did not increase the risk of lupus flares in observational studies (21–23); however, the SELENA group detected a slight increase in the risk of developing mild or moderate, but not severe, flares (24).
We have sought to evaluate the effects of menopause hormonal therapy on disease activity, menopause symptoms, bone mineral density, lipid profile, and mammographic breast density in women with SLE who were in the menopausal transition or in early or late postmenopause. The results described herein focused on the question of whether there is a clinically significant difference in lupus activity (25), as measured by the SLE Disease Activity Index (SLEDAI) (26), in women receiving menopause hormonal therapy in comparison with women taking placebo. The study followup was completed prior to the publication of the WHI study, and data about other outcomes will be presented in future studies.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
We evaluated the effects of menopause hormonal therapy as compared with placebo on disease activity in women with SLE who were in the menopausal transition or in early or late postmenopause. Over 24 months of followup, disease activity remained mild and stable, and no clinically significant difference was seen between treatment groups.
Disease activity was assessed by a validated measure that was sensitive to change over time (26), and the incidence of flares was estimated using a validated definition (31). We also analyzed disease activity according to the SLEDAI-2K (32) and M-SLEDAI, and in the subgroup of patients with active disease at entry. The results of these analyses were similar to those of the primary analyses. We believe that the assessments of disease activity were adequate and that menopause hormonal therapy does not increase lupus activity to a clinically significant degree. Our results are consistent with those of observational studies of menopause hormonal therapy (21–23), our clinical trial of contraceptive methods in women with SLE (19), and the contraception trial conducted by the SELENA group (20), in which no increase in disease activity was observed.
Recently, the SELENA group, using the same hormone regimen in postmenopausal women, found that the rate of severe flares and the mean change in the activity index score were not different between women who received menopause hormonal therapy and those who received placebo; nevertheless, women receiving menopause hormonal therapy experienced an increased rate of mild or moderate flares (24). In our study, although the number of patients with flares and the probability of flares tended to be higher among women receiving menopause hormonal therapy, especially when the lupus was active at baseline, the incidence rate of flares was similar in both groups. The difference in these results might be explained by the more sensitive definition of flare, the larger number of patients, or the higher rates of stopping the study medication and loss to followup (35% for the menopause hormonal therapy group and 27% for the placebo group) in the SELENA trial in comparison with our study. Nevertheless, this statistical difference is not clinically relevant and overall, these studies show that the use of menopause hormonal therapy by women with SLE does not elicit disease exacerbation.
Disease activity in the study population was mild/moderate at entry; since we did not restrict study participation unless the SLEDAI score was >30, and no patient was rejected for this reason, this result reflects the mildness of lupus activity at various postreproductive stages (33, 34). So, we consider that the population studied represents most women with SLE in the menopausal transition or in early or late postmenopause, in terms of disease activity.
Although the risk–benefit profile of menopause hormonal therapy has been established by the results of the HERS and the WHI trials (3, 4), the population included in those studies does not exactly correspond with that included in this study. Our population was composed of younger women, half of whom were in the menopausal transition or in early postmenopause (28), when menopause symptoms are most severe and bone loss is accelerated.
No differences in adverse events were observed between treatment groups in this study. However, the study was not adequately powered to detect differences in the incidence rates of most adverse events between the groups.
A result from our study and the SELENA trial (24) that is worth discussion is that thrombotic events occurred more often and at an identical ratio (3:1) in women receiving menopause hormonal therapy than in those receiving placebo. This result is consistent with results of observational studies (35–37) and clinical trials (4) of the use of menopause hormonal therapy among healthy women. Also, in our trial of contraceptive methods in women with SLE, thrombosis occurred only among women assigned to hormonal methods (2 patients in the combined oral contraceptives group and 2 in the progestin-only pill group); none occurred in the copper intrauterine device group (19).
Thrombosis is unusual in the general population. The incidence rate among women ≤30 years of age is 0.05 per 1,000 person-years (38), and in postmenopausal women, it is 0.08–0.11 per 1,000 person-years (35–37). In stark contrast, thrombosis has been reported in 10–20% of lupus patients (39–41), and the incidence rate among patients in whom the disease is prevalent is 5.1 per 1,000 patient-years (39) and up to 51.9 per 1,000 patient-years in an inception cohort of lupus patients (40). Considering that the use of exogenous estrogens is associated with a thrombosis RR of 2.1–3.6 (35–37), the absolute risk imposed by menopause hormonal therapy in women with SLE seems to be unacceptable. In our study, 1 episode of thrombosis was observed among every 28 women who received menopause hormonal therapy.
Avoiding menopause hormonal therapy in women who are positive for aPL would not be enough, since other factors, such as smoking, older age, disease activity over time, and glucocorticoid dose, are also associated with the occurrence of venous thrombosis in lupus patients (42). Therefore, we consider the real threat of menopause hormonal therapy in women with SLE to be the risk of developing thrombosis, not the effect of menopause hormonal therapy on disease activity. Whether this hazard can be diminished by alternative routes of estrogen administration or preparations of lower dosages needs to be explored.
Our study has several limitations. Since women who had previously received menopause hormonal therapy were allowed to participate, a selection bias toward women in whom this therapy was safe and well tolerated may exist. Nevertheless, the percentage of women who received menopause hormonal therapy in the past was similar between those who declined to participate and those who enrolled in the study; thus, we do not consider that this situation influenced our results.
We used a continuous-sequential estrogen-progestogen regimen, in which medroxyprogesterone acetate may attenuate estrogen's proinflammatory effects (43); therefore, our results should not be extrapolable to regimens containing only estrogens. The present trial evaluated the effect of a continuous-sequential estrogen-progestogen regimen on lupus activity during most of the recommended period of treatment for menopause symptoms; however, the risks and benefits of long-term use in SLE patients still need to be addressed. Treatment of SLE was administered at the discretion of the rheumatologist, and no differences in the treatment administered between the patient groups were evident at entry or throughout the followup period. Because this study was conducted at a single center with limited ethnic variation among the patients, one must be circumspect about extrapolating the results to all women with SLE. However, our results are consistent with those of studies conducted in populations of other ethnicities (21–24).
Our study was a nonequivalence trial; however, considering the actual level of disease activity in the study population at baseline, the sample size we achieved provided a 90% chance of detecting a difference in the SLEDAI score of ≥2.10, instead of the originally planned 3.0. Therefore, although we did not detect any clinically significant differences in disease activity (25) between treatment groups, the study had limited power to detect a smaller difference. The study was underpowered to assess the risk for cardiovascular events, cancer, and other disorders associated with menopause hormonal therapy. Also, in this report we do not describe the effects of this therapy on menopause symptoms, bone mineral density, lipid profile, and mammographic breast density in women with lupus. Such analysis is under way.
Some strengths of our study also need to be considered. The participation rate throughout the trial was high, and the adherence to treatment was assessed by estradiol measurements. We offered participation in the study to all women with SLE at different postreproductive stages, including the menopausal transition and early or late postmenopause (28), who attended our center, including those with variable disease activity and those who tested positive for aPL, provided they had no history of recent thrombosis. Twenty-seven percent of the patients had undergone premature menopause, and the mean BMI was <27 kg/m2. Our patients were all Mexican women, and we think the results can be generalized to most Hispanic women with SLE at different menopause-related stages.
In conclusion, since women with SLE are at an increased risk of developing premature menopause (2), osteoporotic fractures (44), cognitive dysfunction (45), premature atherosclerosis (46), thrombosis (40), and cardiovascular events (47), and their quality of life often is poorer than that of the general population (48), the effects of menopause in addition to these conditions, and the risk–benefit profile of menopause hormonal therapy in these women and those with other chronic diseases, need to be explored in depth. Menopause hormonal therapy did not affect the course of disease activity, at a clinically significant level, in women with SLE who were in the menopausal transition or in early or late postmenopause. Nonetheless, the potential increase in the risk of developing thrombosis may outweigh any benefits.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Sánchez-Guerrero had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Sánchez-Guerrero, González-Pérez, Cravioto.
Acquisition of data. Sánchez-Guerrero, González-Pérez, Durand-Carbajal, Lara-Reyes, Jiménez-Santana, Cravioto.
Analysis and interpretation of data. Sánchez-Guerrero, González-Pérez, Durand-Carbajal, Lara-Reyes, Jiménez-Santana, Romero-Díaz, Cravioto.
Manuscript preparation. Sánchez-Guerrero, González-Pérez, Durand-Carbajal, Lara-Reyes, Jiménez-Santana, Romero-Díaz, Cravioto.
Statistical analysis. Sánchez-Guerrero, Romero-Díaz, Cravioto.