The Contraceptive Depot Medroxyprogesterone Acetate Impairs Mycobacterial Control and Inhibits Cytokine Secretion in Mice Infected with Mycobacterium tuberculosis

Abstract

dThe contraceptive depot medroxyprogesterone acetate (DMPA), with progestin as the single active compound, possesses selective glucocorticoid activity and can alter the expression of glucocorticoid receptor-regulated genes. We therefore propose that pharmacological doses of DMPA used for endocrine therapy could have significant immune modulatory effects and impact on susceptibility to, as well as clinical manifestation and outcome of, infectious diseases. We investigated the effect of contraceptive doses of DMPA in two different murine Mycobacterium tuberculosis models. Multiplex bead array analysis revealed that DMPA altered serum cytokine levels of tumor necrosis factor alpha (TNF-␣), granulocyte colony-stimulating factor (G-CSF), and interleukin 10 (IL-10) in C57BL/6 mice and gamma interferon (IFN-␥) in BALB/c mice. DMPA also suppressed antigen-specific production of TNF-␣, G-CSF, IL-10, and IL-6 and induced the production of IP-10 in C57BL/6 mice. In BALB/c mice, DMPA altered the antigen-specific secretion of IFN-␥, IL-17, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and monocyte chemotactic protein 1 (MCP-1). Furthermore, we show that C57BL/6 mice treated with doses of DMPA, which result in serum concentrations similar to those observed in contraceptive users, have a significantly higher bacterial load in their lungs. Our data show for the first time that DMPA impacts tuberculosis (TB) disease severity in a mouse model and that the effects of this contraceptive are not confined to infections of the genital tract. This could have major implications for the contraceptive policies not only in developing countries like South Africa but also worldwide.

Effect of progestins on immunity: medroxyprogesterone but not norethisterone or levonorgestrel suppresses the function of T cells and pDCs

“…This study confirms that MPA suppresses innate and adaptive immune mechanisms at a physiological concentration [5, 20, 22, 26, 28, 29]. MPA inhibited the production of IFNγ, IL-1β, IL-4, IL-13, GM-CSF, and TNFβ by TCR-activated T cells and reduced the production of IFNα and TNFα by pDCs in response to stimulation with HIV-1 and TLR-7/8 and 9 ligands.…”

Differential Glucocorticoid Receptor‐Mediated Effects on Immunomodulatory Gene Expression by Progestin Contraceptives: Implications for HIV‐1 Pathogenesis

“…We did not detect substantial GILZ expression in monocytes or IL6 expression in CD4 + T cells. These results showing immunosuppressive effects of MPA on gene expression are consistent with our previous data, [31][32][33] as well as with results reported by others in Bacillus Calmette-Guerin-stimulated PBMCs and murine M. tuberculosis models, 41,42 and those from the Hel laboratory in activated T cells and in primary vaginal mucosal mononuclear cells (VMMCs) 36 and cytobrushes from patients on DMPA. 36 To investigate the role of the GR in mediating the responses, PBMCs were treated with DEX and MPA in the absence and presence of RU486, a known GR antagonist.…”

Is a lower-dose, subcutaneous contraceptive injectable containing depot medroxyprogesterone acetate likely to impact women's risk of HIV?

“…This may occur despite no apparent effect on other side-effects, if these biological responses are more sensitive to changing serum concentrations of MPA (different EC50 values). Importantly, possible reduction of MPA Cmax concentrations for DMPA-SC versus DMPA-IM is not likely to ameliorate the impact of MPA on biological responses with EC50 values below 1 nM [66–68]. …”