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

Abstract

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, HIVnegative 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 IFNγ, TNFα, IL-4 and IL-13.Results: Compared with baseline, decreased proportions of IFNγ-producing CD4+ and CD8+ T cells (p = .003, p = .006, respectively) and TNFα-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 IFNγ, TNFα 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.

Hormonal contraceptive use and the risk of sexually transmitted infections: a systematic review and meta-analysis

“…Research has examined the relationship between DMPA and Norethisterone enanthate use and the impact of immune cell responsiveness to identify whether using these POC may increase susceptibility to infections. However, in a study by Matubu et al 62 the exposure of CD4 + and CD8 + T cells to typical pharmacologic concentrations of DMPA was not found to cause immunosuppressive effects. Despite this, the depletion of cytokine-producing T cells may occur after prolonged DMPA use.…”

The Progestin Medroxyprogesterone Acetate Affects HIV-1 Production in Human Lymphoid Tissue Explants in a Dose-Dependent and Glucocorticoid-like Fashion

“…Although the dosedependency of this effect is clear, we cannot exclude that a transient reduction of the local immune defenses upon MPA administration in vivo, possibly involving cell apoptosis, is followed by inflammatory processes such as cell recruitment and activation, including CCR6-and CCR5-expressing HIV-1 target cells [45]. While attempting to mirror declining plasma levels of MPA upon injection, our model cannot recapitulate any potential long-term changes nor the impact of a prolonged use of MPA following multiple injections [46], owing to intrinsic limitations in tissue explant integrity/viability over time [21]. Multiple cell subsets and soluble factors likely contribute to the observed structural changes in the FGM of DMPA users, including stromal and epithelial cells and related growth factors [25,47].…”

Genital inflammatory status and the innate immune response to contraceptive initiation

“…Sex steroid hormones are inherently linked to the regulation of microbial populations in the FGT 42 . While endogenous oestrogen and its synthetic analogue estradiol have previously been associated with an increased abundance of beneficial Lactobacillus species, 43 the findings of previous studies on the effects of progestin‐only contraceptives, such as DMPA‐IM, on vaginal microbial communities have been inconsistent 22,44–50 . The injectable has also been linked to altered cell‐mediated immune responses, which in turn increase a woman's susceptibility to BV and STIs, including HIV.…”

“… 42 While endogenous oestrogen and its synthetic analogue estradiol have previously been associated with an increased abundance of beneficial Lactobacillus species, 43 the findings of previous studies on the effects of progestin‐only contraceptives, such as DMPA‐IM, on vaginal microbial communities have been inconsistent. 22 , 44 , 45 , 46 , 47 , 48 , 49 , 50 The injectable has also been linked to altered cell‐mediated immune responses, which in turn increase a woman's susceptibility to BV and STIs, including HIV. Recently, it has been demonstrated that effects of DMPA‐IM on genital inflammatory pathways may be modified by the FGT microbiome.…”