Immunotherapy for Fertility in Autoimmune Premature Ovarian Insufficiency

BACKGROUND: Women with autoimmune diseases have an increased risk of premature ovarian insufficiency (POI), leading to early menopause and infertility. We hypothesized that B-cell depletion with rituximab could reverse autoimmune activity, enhance ovarian responsiveness to gonadotropins, and transiently restore fertility in autoimmune POI. METHODS: In this proof-of-concept study, we enrolled women between the ages of 18 and 35 years with autoimmune POI. Each participant underwent controlled ovarian hyperstimulation before and 4 to 6 months after treatment with rituximab (two 1-g infusions, administered 2 weeks apart). Participants were followed for 12 months after rituximab infusion. The primary outcomes of interest were the number of antral follicles and the size of the largest follicle in response to ovarian stimulation. In the case of successful oocyte retrieval, oocytes were cryopreserved or fertilized. For safety, embryo transfer was deferred until at least 12 months after rituximab administration. RESULTS: We enrolled 12 women, with a mean (standard deviation) age of 30.8 (2.8) years. Two women withdrew consent prior to initiating the study. Prior to rituximab, none of the participants responded to ovarian hyperstimulation with follicular development. Following rituximab, after undergoing another ovarian hyperstimulation, follicular development occurred in six women that led to oocyte retrieval (responders). In three of these cases, oocytes were fertilized and embryos preserved; all three women subsequently delivered healthy children. One serious adverse event occurred during the trial, related to ovarian hyperstimulation. CONCLUSIONS: In this small proof-of-concept study with no control group, of 10 women with premature ovarian insufficiency who received rituximab followed by ovarian stimulation, six underwent oocyte retrieval. A randomized controlled trial is needed to further evaluate this treatment strategy. (Funded by the Swedish Research Council and others; EudraCT number, 2017-004532-10; ClinicalTrials.gov number, NCT05586737.).