Effect of injectable progestin-only contraceptives, depot medroxyprogesterone acetate and norethisterone enanthate, on cytokine production during T-cell activation.

PROBLEM: There is paucity of human data about the effects of depot medroxyprogesterone (DMPA) and norethisterone enanthate (Net-En) use on systemic immune function, which may have implications for reproductive tract infection susceptibility and transmissibility. We sought to evaluate the impact of injectable contraceptive use on T-cell responsiveness using T cells exposed in vivo and tested ex vivo. METHODS: Peripheral blood mononuclear cells were obtained from healthy, HIV-negative women after 30, 90 and 180 days of DMPA, norethisterone enanthate (Net-En) or copper intrauterine device (Cu-IUD) contraceptive use. Cells were stimulated ex vivo with phorbol myristate acetate and ionomycin, stained and analysed using flow cytometry. Mixed-effects linear models were used to evaluate change in proportions of T cells producing IFN-γ, TNF-α, IL-4 and IL-13. RESULTS: Compared with baseline, decreased proportions of IFN-γ-producing CD4+ and CD8+ T cells (p = .003, p = .006, respectively) and TNF-α-producing CD4+ and CD8+ T cells (p = .039, p = .034, respectively) were observed after 180 days of DMPA use. Decreased IL-4-producing CD4+ and CD8+ T cells (p = .045 and p = .024, respectively) were noted after 180 days of Net-En use. Decreased IL-4-producing CD4+ T cells were observed after 30 days (p = .035) and not after 180 days of DMPA use (p = .49). There were no changes in proportion of T cells producing IL-13 in DMPA users, nor any changes in IFN-γ, TNF-α and IL-13 in Net-En and Cu-IUD users. CONCLUSION: In vivo exposure of CD4+ and CD8+ T cells to typical pharmacologic concentrations of DMPA does not cause broad suppression to stimuli; however, depletion of specific cytokine-producing T cells may occur after prolonged DMPA use.

Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T-cell responses and expression of immunosuppressive markers.

PROBLEM: Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En). METHOD OF STUDY: Peripheral blood mononuclear cells collected from women aged 18-34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4). RESULTS: Compared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+ T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed. DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline. CONCLUSION: Activation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient.

An Assessment of the Effectiveness of Warfarin Therapy Monitoring Systems on Thrombophilic Patients in Zimbabwe.

Introduction Thrombophilia describes conditions that predispose individuals to increased blood clotting and includes conditions such as deep vein thrombosis and pulmonary embolism. Thrombophilia is associated with high morbidity and mortality rates, and is commonly treated by warfarin anticoagulation. However, warfarin may cause both bleeding and clotting episodes if the therapy is not monitored and managed effectively. Objectives The main objective of this study was to assess the effectiveness of warfarin monitoring systems on thrombophilic patients at a major hospital in Zimbabwe. Material and Methods A clinical and laboratory prospective and retrospective study was performed on patients who had been on warfarin therapy for at least 1 year. Questionnaires were administered to participants on warfarin from outpatients clinics at Parirenyatwa Group of Hospitals. Their international normalized ratio (INR) results were also accessed from the laboratory information system and captured in the Epi info and Microsoft Excel for analysis. Results Fifty questionnaires were administered and 47 (94%) participants responded adequately. Twenty-nine (61.1%) participants on warfarin were females. The majority of them were elderly and in the 31 to 40 age groups. Eighteen (38.3%) participants missed their medication at some point, while 12 (25.5%) had warfarin overdose. Sixteen (34%) and 11 (23.4%) admitted to taking alcohol and smoking, respectively, while on warfarin. Thirty-five (74.5%) did not change their medication nor were advised on the right diet. Thirty-four (72.3%) had appointments set after every month. Some participants indicated that they had symptoms of both clotting and bleeding. There were statistically significant differences ( p < 0.0001) between INRs for 3 monthly intervals from the initiation of warfarin therapy. Conclusion Women and the elderly formed the majority of the patients on warfarin, indicating gender and advanced age susceptibility to thrombophilia, respectively. The effectiveness of the warfarin monitoring systems appeared to be hampered by lack of a coordinated system that adequately monitors anticoagulant therapy in the country.