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

Abstract

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 aged18-34 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. K E Y W O R D S depot medroxyprogesterone acetate, norethisterone enanthate cytotoxic T-lymphocyte associated protein-4, programmed cell death-1 How to cite this article: Matubu A, Hillier SL, Meyn LA, et al. Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T-cell responses and expression of immunosuppressive markers. Am J Reprod

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

“…Findings from our two studies suggest T cell-related immune system changes that occur in DMPA users and that could impact susceptibility to infections including HIV, consistent with in vitro studies demonstrating reduction in T-cell release of IFNγ and TNFα following MPA exposure. [19][20][21]26 However, we also demonstrated that physiologic exposure to DMPA did not significantly reduce the proportion of IL-4-and IL-13-producing T cells after six months of use, a finding that differs from published studies of T cells exposed to MPA in vitro. 21,22,31 Following intramuscular injection with 150 mg DMPA, serum MPA concentrations rise to ~25 ng/ml within days and decline to between 1-9 ng/ml over the subsequent 12-week dosing period.…”

“…We also reported that T-cell response to ex vivo stimulation is suppressed at steadystate MPA concentrations and resolves at nadir concentration suggesting transient immunosuppression. 26 The results presented here further our prior work and demonstrate that after 180 days of injectable contraceptive use, at nadir hormone concentrations, physiologically exposed T cells have depleted cytokine production. Findings from our two studies suggest T cell-related immune system changes that occur in DMPA users and that could impact susceptibility to infections including HIV, consistent with in vitro studies demonstrating reduction in T-cell release of IFNγ and TNFα following MPA exposure.…”

“…This sub-study was conducted using samples collected as part of a larger prospective cohort of healthy, reproductive-aged Zimbabwean women seeking contraception who enrolled into the Zim CHIC Detailed descriptions of Zim CHIC study participants have been previously published. 25,26 This study was approved by the Medical Research Council of Zimbabwe (MRCZ/A.2133) and the University of Pittsburgh (STUDY19050079) Institutional Review Boards. All participants were enrolled at Spilhaus Family Planning Center in Harare, Zimbabwe, and signed informed consent before study participation.…”

Sexual behaviour among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: Data from the ECHO randomized trial

“…For example, the etonorgestrel implant has been associated with impaired sexual function, thought to be related to suppression of estrogen and testosterone [ 20 ], but we do not have robust data comparing this effect with other methods. Intramuscular norethisterone enanthate has many similar behavioural effects to DMPA-IM, but less glucocorticoid and immunosuppressive effects] [ 21 , 22 ]. This might confer a similar reduction in exposure without increased immune susceptibility and thus lower net risk of HIV.…”

Female Sex Hormones Upregulate the Replication Activity of HIV-1 Sub-Subtype A6 and CRF02_AG but Not HIV-1 Subtype B

“…The methods of hormonal contraception such as intramuscular DMPA injections, copper intrauterine spirals, and levonorgestrel implants were considered safe. However, despite the updated WHO guidelines, the use of DMPA remains controversial and raises questions among specialists, since extensive clinical and laboratory data indicate that this contraceptive can still increase the risk of HIV infection [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. A number of epidemiological studies indicate that women living with HIV-1 who use hormonal contraception, compared with HIV-positive women who do not, have a significantly higher viral load, simultaneous infection with several HIV-1 genotypes, and more accelerated CD4+T cell loss, which correlates with increased mortality among this cohort [ 14 , 31 , 32 , 33 , 34 ].…”