The use of AMH is gaining support as a sensitive and non-invasive measure of ovarian function12
. Because it is measured on a continuous scale, AMH better approximates gradations in ovarian reserve, and at earlier points in the natural history, thus providing insight beyond conventional endpoints like POI.
In the current study, we compared AMH levels from SLE patients who had previously received gonadotoxic medication with those from SLE patients who never received CYC and therefore had less severe disease, and from those with GnRH-a co-treatment during CYC therapy. As expected, AMH levels were significantly lower in the women who received CYC alone compared to those without CYC exposure, which may also reflect an association between heightened SLE activity and disease duration with ovarian insufficiency 22
. While AMH levels were also lower among SLE patients who received CYC + GnRH-a compared to SLE patients with no CYC exposure, the difference was of lower magnitude than for women treated with CYC alone. Taken together, our results suggest that GnRH-a co-treatment may offer partial protection against ovarian damage in women receiving CYC for severe SLE.
Consensus among experts regarding potential benefit of GnRH-a therapy for ovarian protection among women receiving chemotherapy is lacking. 23-26
Clinical trials of GnRH-a in populations undergoing heterogeneous chemotherapeutic protocols report encouraging results3,8,10,11,27
, as has a recent meta-analysis, inclusive of 320 patients from seven controlled studies, which found GnRH-a use during chemotherapy was significantly associated with ovarian function preservation (RR 1.7; 95% CI 1.4-2.2)28
. However, GnRH-a failed to significantly impact the rate of ovarian insufficiency during chemotherapy in other studies12,29
, and a recent clinical review found insufficient evidence of any protective effect of GnRH-a therapy24
Results from our retrospective study add to supportive evidence for GnRH-a therapy by showing that AMH, arguably the most reliable biomarker of ovarian reserve, is more preserved with GnRH-a therapy after CYC, and that GnRH-a provides at least partial ovarian protection during alkylating agent monochemotherapy in a cohort of lupus patients. These results may not be applicable to other patient populations receiving aggressive anti-neoplastic treatment regimens with more than one alkylating agent.
Study limitations include small sample size and retrospective nature. Additionally, average baseline AMH was lower among patients receiving CYC alone compared to CYC plus GnRH-a, raising the possibility that unknown factors were involved that we were unable to measure. However, neither age nor cumulative CYC dose at baseline were statistically different between the two groups. We did not adjust for baseline AMH measures due to the observational nature of this study; in non-randomized studies, adjustment for baseline measures could result in erroneous conclusions when the assumption of equal population distributions of the baseline predictor is not met 30
, as was the case for AMH between the three treatment groups in this study. Adjustment for baseline AMH would address a different scientific question that would be related to the group differences given that the individual has the same baseline AMH measure. A randomized trial would more adequately ensure baseline comparability between groups. A final limitation is that sera were not uniformly available prior to the initial time of CYC exposure, which would be important for demonstrating rate of decline of AMH after CYC exposure. The rate may be similar to the rapid and consistent decline of AMH levels from pretreatment levels observed in a study of breast cancer patients, as early as three months after initiation of polychemotherapy31
Data from our study add support to the hypothesis that GnRH-a co-therapy mitigates chemotherapy-induced gonadotoxicity. Prospective, randomized, controlled trials are indicated to confirm these results, and to enable detailed investigation of longitudinal trends in AMH, cumulative dose effects of CYC, and interaction between dose and age.