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

Abstract

Objectives: The potential effect of hormonal contraception on HIV-1 acquisition and transmission represents an important public health issue. Several observational studies have suggested an association between the use of hormonal contraception, in particular injectable depot medroxyprogesterone acetate (DMPA), and an increased risk of HIV-1 acquisition and transmission. We and others have previously demonstrated that DMPA acts as a potent inhibitor of innate and adaptive immune mechanisms. The study presented here addresses the immunomodulatory properties of several common progestins with a potential to replace DMPA.

Study design: To identify safe alternatives to DMPA, we tested the effect of commonly used progestins on the function of human primary T cells and plasmacytoid dendritic cells (pDCs) obtained from the blood of healthy premenopausal women.

Results: Medroxyprogesterone acetate (MPA) inhibited the activation of T cells and pDCs in response to T cell receptor- and Toll-like receptor-mediated activation at physiological concentrations. Etonogestrel exerted a partial suppressive activity at high concentrations. In sharp contrast, norethisterone (NET) and levonorgestrel (LNG) did not exhibit detectable immunosuppressive activity.

Conclusion: Evidence indicating the immunosuppressive properties of DMPA strongly suggests that DMPA should be discontinued and replaced with other forms of long-term contraception. Since NET and LNG do not exert immunosuppressive properties at physiological concentrations, these progestins should be considered as alternative contraceptives for women at high risk for HIV-1 infection.

Implications: The presented data suggest that, at physiological levels, the progestins NET and LNG do not suppress cytokine production by immune cells and should be considered as alternatives to DMPA; however, more in vivo testing is needed to confirm this data.

Keywords: AIDS; DMPA; ETG; HIV-1; Hormonal contraception; LNG; NET; Progestins.

Figure. 1. MPA but not NET or LNG suppresses cytokine production by activated mononuclear cells and pDCs

A) PBMCs obtained from healthy female volunteers were incubated for 24 hrs in the presence of vehicle (Veh; DMSO) or indicated concentrations of progestins and activated for an additional 24 hrs with microbeads coated with antibodies against CD2, CD3, and CD28 antigens. Graph represents the concentration of IFNγ in the culture media. Data are normalized values relative to vehicle control; mean ± standard error of the mean (SEM) of three donors is shown. B) Heat map representation of the effect of P4, MPA, and NET on cytokine production by mononuclear cells stimulated with microbeads coated with antibodies against CD2/CD3/CD28. Data are presented as normalized values relative to vehicle; means of three independent experiments are presented. * denotes statistically significant difference (p < 0.05) compared to P4-treated samples at respective concentrations. C) Graphic representation of the effect of P4, MPA, NET, LNG, and ETG at the indicated concentrations on intracellular production of IFNα and TNFα by pDCs stimulated with AT2-inactivated HIV-1, R848, or CpG. Normalized data from three independent donors corrected for background are presented. D) Effect of P4, MPA, and NET on the accumulation of IP-10 (CXCL10) and MCP-1 in cell culture supernatants of HIV-1-stimulated PBMCs. Data from three independent experiments are normalized to vehicle control ± SEM. P4, progesterone; MPA, medroxyprogesterone acetate; NET, norethisterone; LNG, levonorgestrel; ETG, etonogestrel. * denotes statistically significant difference (p < 0.05) of progestin-treated samples compared to the P4-treated samples.