Discussion
Our analysis shows a slight reduction in AMH values after controlling for age, BMI and hormonal contraception use even among women with SLE who had never been treated with CYC. Women with SLE were 1.5–1.6 times as likely to have low values of AMH compared with women without SLE. Our plot of predicted values suggested that this difference was more pronounced at younger ages. This suggests an association between SLE and ovarian insufficiency. Diminished ovarian reserve may be caused by several different mechanisms among women with SLE, including autoimmune oophoritis, where autoantibodies target parts of the ovary which in turn causes ovarian inflammation and reduced follicle counts.29 While we were unable to examine disease damage in our study population, several studies have noted that high damage scores are associated with lower AMH levels.10 30 Our results are in contrast to a few studies that did not find an association between AMH and SLE without a history of CYC treatment.10 17 Our result is supported by a recent meta-analysis that did find an association between AMH and SLE among women not treated with CYC, although the authors noted that their pooled results were heavily influenced by one study that showed a very strong association.31
Previously, AMH was thought to be predictive of a woman’s ability to conceive. More recent studies, however, suggest that AMH is not associated with time to pregnancy in women attempting to conceive or necessarily lower in women who have reported infertility.11 32 33 However, AMH is valuable clinically as predictive of how well a woman will respond to fertility treatments. Assisted reproductive technologies are both considered safe in women with SLE with stable disease, and important to consider as women with SLE may be more likely to experience infertility, as shown in another paper by our group.34 35 Low AMH has also been identified as a predictor of time to menopause, including early menopause, defined as menopause before age 45 years.7 8 Time to menopause is important among women seeking or eventually seeking pregnancy as their fertile window may be shorter if menopause occurs early. In addition, time to menopause may also be a predictor of other health outcomes. It is generally shown that women with early menopause are also at an increased risk of cardiovascular disease.36 While the mechanism underlying the increased risk of cardiovascular disease after menopause remains controversial, low and/or declining levels of AMH have been shown to be associated with cardiovascular disease overall as well as coronary heart disease.37 38 Women with SLE who are diagnosed at younger ages or have been treated with CYC have been shown to be at risk of early menopause.39 As these women with SLE may be at greater risk of early menopause and women with SLE are already at greater risk of early cardiovascular disease than the general population, there is a need to examine how AMH, a potential predictor of early menopause, compares in women with SLE relative to the general population.40 41
Like other studies, we found that AMH is substantially lower among women with SLE who had been treated with CYC.10–13 While our sample of women treated with CYC was small, they were noticeably younger than both women with SLE who had not been treated with CYC and the comparison women, yet still had substantially lower AMH values. When predicted values of AMH were plotted by age, women treated with CYC appeared to have AMH values comparable to much older women not treated with CYC. This is also demonstrated where nearly all of the women treated with CYC younger than 35 years had AMH levels below the 25th percentile of the comparison group. It is well-established that CYC is a gonadotoxic agent that causes ovarian damage.42 At present, evidence of the effectiveness of gonadotropin-releasing hormone agonists (GnRH-a) for fertility preservation among women receiving CYC is not strong.43 44 It is also suggested that adolescents with SLE do not always receive fertility counselling prior to receiving gonadotoxic treatments.45 More work is needed to discern an effective counselling protocol for women with SLE receiving potentially gonadotoxic treatments.
Our analysis has several limitations that should be noted. First, we had a relatively small number of participants, especially when considering those exposed to CYC and those at the ends of the age distribution (<24 and >37 years). However, our study still represents the largest study of AMH among African-American women with SLE. Second, we did not have information on the cumulative dose or timing of CYC treatment, which has been shown to be negatively associated with AMH.12 We also did not have information on if women treated with CYC had also received GnRH-a therapy. In addition, women treated with CYC likely have more severe disease than women with SLE who were never treated with CYC. We cannot distinguish between the effect of disease severity and CYC among women treated with CYC, so there may be confounding by indication. However, the confounding effect of disease severity would likely need to be extremely strong to fully account for the association between CYC and AMH levels.46 By excluding women currently receiving kidney dialysis, we also have potentially excluded women with severe SLE. Finally, some research has suggested that individual trajectories of AMH over time are more salient predictors of important health outcomes than population-level averages by age.38 47 As this was a cross-sectional study, we were unable to examine individual trajectories of AMH over time.
This is the only study to have specifically examined AMH among African-American women with SLE. We were able to distinguish between women with SLE who had been treated with CYC and those that had not, and also included a comparison group of women without SLE. Our research suggests that even women with SLE not treated with CYC may have lower levels of AMH than women without SLE. This suggests that both the disease and treatment of SLE negatively impacts ovarian reserve and long-term ovarian function. Future research should examine trajectories of AMH in women with SLE with repeated measurements. In addition, the ability of AMH to predict other health outcomes, such as cardiovascular disease and the onset of early menopause among women with SLE, should be explored further.