Effects of Methotrexate Therapy on the Levels of Gonadotropic Hormones in Rheumatoid Arthritis Patients of Reproductive Age

Background: Methotrexate (MTX), which is the anchor drug in rheumatoid arthritis (RA), targets actively proliferating cells including the oocytes and granulosa cells which may impair the ovarian reserve. The purpose of this study was to determine the effects of MTX therapy on gonadotropic hormones, i.e. follicular stimulating hormone (FSH) and luteinizing hormone (LH) in female RA patients of reproductive age. Materials and methods: This is a cross-sectional study conducted at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC), from January 2018 to July 2018. Women with RA aged between 15 and 49 years who were on MTX therapy for at least six months, were consecutively recruited. All subjects were interviewed to gather information on their menstrual history and menopausal symptoms. The medical records were reviewed to obtain further data on the disease characteristics and RA treatment. The RA disease activity was determined using the DAS 28 scoring system. All subjects were tested for their serum FSH and LH levels. Results: A total of 40 patients were included in this study. The median dose of MTX used by the subjects was 12.5 mg weekly. The mean cumulative MTX dose was 1664.92 ± 738.61 mg. More than half (53.1%) of the subjects reported menopausal symptoms especially hot flushes. We found that FSH levels had a significant positive correlation with cumulative MTX dose [(r = 0.86), p < 0.001] and the duration of MTX therapy [(r = 0.84), p < 0.001]. Besides, there was a significant relationship between disease activity based on DAS 28 and FSH levels (p < 0.01). Age, body mass index, disease duration, and weekly MTX dose showed no associations with the FSH levels. On multivariate analysis, DAS 28 was found to be the only parameter that remained significant [β = 1.74 (95% CI 1.17-2.31), p < 0.001]. The LH levels, on the other hand, were not associated with MTX therapy or disease activity. Conclusion: Higher levels of FSH, which is an indicator of diminished ovarian reserve, have a significant positive relationship with disease activity, cumulative dose, and duration of MTX therapy in RA.